Academic literature on the topic 'Immunosuppression. eng'

Abstract Background A two-dose hepatitis B (HBV) vaccine with an immunostimulatory adjuvant (HBV-ISS, Heplisav-B), was FDA approved in 2017 for adults 18 years and older. In randomized controlled trials (RCTs), HBV-ISS demonstrated a seroprotection rate (SPR) of 90–95% versus 65–80% for Engerix-B (HBV-Eng). No RCTs, however, included people with HIV (PWH), and the SPR and its predictors in this population are unknown. Methods This retrospective cohort study enrolled PWH ages 18 years and older without current HBV seroprotection at an HIV clinic at a tertiary care center. HBV seroprotection was defined as an anti-HBV surface antibody level >= 10 mIU/mL. Patients without follow-up titers after immunization were excluded. The primary outcome was the SPR, the proportion of patients with HBV seroprotection at any point following the first HBV-ISS vaccination. Results Among the 51 PWH included, 50 received 2 doses of HBV-ISS (1 patient who received 1 dose developed seroprotection) (Table 1). Median time to antibody titer measurement was 11 weeks (IQR 7–19 weeks). Median age was 59 years, 90% were men, and 96% had VL < 200. There were no pregnant or breastfeeding patients. The SPR was 82% (42/51) in the cohort, and 86% (38/44) when patients with significant non-HIV immunosuppression (decompensated cirrhosis, solid organ transplantation, active chemotherapy) were excluded. There were no significant differences in SPR based on age, sex, BMI, diabetes mellitus, chronic kidney disease, history of remote anti-HBV surface or core antibody positivity, or prior HBV vaccination (Table 2). Lower current and nadir CD4+ counts were associated with progressively lower SPRs (P for trend < 0.0001 for both) (Figure 1). Table 1. Baseline Demographics and Characteristics Table 2. Seroprotection Rate (SPR) by Variables of Interest Figure 1. Seroprotection Rate (SPR) by Current and Nadir CD4+ Count Conclusion The SPR from HBV-ISS in PWH appears comparable to the immunocompetent patients included in RCTs, especially when patients with significant non-HIV immunosuppression are excluded. The SPR demonstrated in this single-arm, retrospective study was higher than that of HBV-Eng in immunocompetent patients, and consideration should be given to establishing HBV-ISS as first-line HBV vaccination in PWH. Finally, SPR is significantly reduced in those with lower current and nadir CD4+ counts. Further research on the effectiveness of a repeat vaccination series or higher dosing in these subgroups is needed. Disclosures Jennifer Cocohoba, PharmD, AAHIVP, BCPS, Viiv (Grant/Research Support)

: Heart transplantation is the standard of therapy for patients with end-stage heart disease. Since the first human-to-human heart transplantation, performed in 1967, advances in organ donation, surgical techniques, organ preservation, perioperative care, immunologic risk assessment, immunosuppression agents, monitoring of graft function and surveillance of long-term complications have drastically increased recipient survival. However, there are yet many challenges in the modern era of heart transplantation in which immunosuppression may play a key role in further advances in the field. A fine-tuning of immune modulation to prevent graft rejection while avoiding side effects from over immunosuppression has been the vital goal of basic and clinical research. Individualization of drug choices and strategies, taking into account the recipient's clinical characteristics, underlying heart failure diagnosis, immunologic risk and comorbidities seem to be the ideal approaches to improve post-transplant morbidity and survival while preventing both rejection and complications of immunosuppression. : The aim of the present review is to provide a practical, comprehensive overview of contemporary immunosuppression in heart transplantation. Clinical evidence for immunosuppressive drugs is reviewed and practical approaches are provided. Cardiac allograft rejection classification and up-to-date management are summarized. Expanding therapies, such as photophoresis, are outlined. Drug-to-drug interactions of immunosuppressive agents focused on cardiovascular medications are summarized. Special situations involving heart transplantation such as sarcoidosis, Chagas diseases and pediatric immunosuppression are also reviewed. The evolution of phamacogenomics to individualize immunosuppressive therapy is described. Finally, future perspectives in the field of immunosuppression in heart transplantation are highlighted.

Abstract Chronic low-grade inflammation is a common hallmark of the aging process and many age-related diseases. There is substantial evidence that persistent inflammation is associated with a compensatory anti-inflammatory response which prevents excessive tissue damage. Interestingly, the inflammatory state encountered with aging, called inflammaging, is associated with the anti-inflammaging process. The age-related activation of immunosuppressive network includes an increase in the numbers of myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and macrophages (Mreg/M2c). Immunosuppressive cells secrete several anti-inflammatory cytokines, e.g., TGF-β and IL-10, as well as reactive oxygen and nitrogen species (ROS/RNS). Moreover, immunosuppressive cells suppress the function of effector immune cells by catabolizing l-arginine and tryptophan through the activation of arginase 1 (ARG1) and indoleamine 2,3-dioxygenase (IDO), respectively. Unfortunately, the immunosuppressive armament also induces harmful bystander effects in neighboring cells by impairing host tissue homeostasis. For instance, TGF-β signaling can trigger many age-related degenerative changes, e.g., cellular senescence, fibrosis, osteoporosis, muscle atrophy, and the degeneration of the extracellular matrix. In addition, changes in the levels of ROS, RNS, and the metabolites of the kynurenine pathway can impair tissue homeostasis. This review will examine in detail the harmful effects of the immunosuppressive cells on host tissues. It seems that this age-related immunosuppression prevents inflammatory damage but promotes the tissue degeneration associated with aging and age-related diseases. Key messages • Low-grade inflammation is associated with the aging process and age-related diseases. • Persistent inflammation activates compensatory immunosuppression with aging. • The numbers of immunosuppressive cells increase with aging and age-related diseases. • Immunosuppressive mechanisms evoke harmful bystander effects in host tissues. • Immunosuppression promotes tissue degeneration with aging and age-related diseases.

The role of immunosuppression in IgA nephropathy (IgAN) is controversial. In the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) Trial, 162 patients with IgAN and proteinuria >0.75 g/d after 6 months of optimized supportive care were randomized into two groups: continued supportive care or additional immunosuppression (GFR≥60 ml/min per 1.73 m2: 6-month corticosteroid monotherapy; GFR=30–59 ml/min per 1.73 m2: cyclophosphamide for 3 months followed by azathioprine plus oral prednisolone). Coprimary end points were full clinical remission and GFR loss ≥15 ml/min per 1.73 m2 during the 3-year trial phase. In this secondary intention to treat analysis, we separately analyzed data from each immunosuppression subgroup and the corresponding patients on supportive care. Full clinical remission occurred in 11 (20%) patients receiving corticosteroid monotherapy and three (6%) patients on supportive care (odds ratio, 5.31; 95% confidence interval, 1.07 to 26.36; P=0.02), but the rate did not differ between patients receiving immunosuppressive combination and controls on supportive care (11% versus 4%, respectively; P=0.30). The end point of GFR loss ≥15 ml/min per 1.73 m2 did not differ between groups. Only corticosteroid monotherapy transiently reduced proteinuria at 12 months. Severe infections, impaired glucose tolerance, and/or weight gain in the first year were more frequent with either immunosuppressive regimen than with supportive care. In conclusion, only corticosteroid monotherapy induced disease remission in a minority of patients who had IgAN with relatively well preserved GFR and persistent proteinuria. Neither immunosuppressive regimen prevented GFR loss, and both associated with substantial adverse events.

Abstract Viral reactivation in hepatitis B surface antigen (HBsAg) carriers undergoing immunosuppressive therapy is well documented. To evaluate the role of lamivudine prophylaxis in Hepatitis B virus (HBV) carriers treated with immunosuppression for nonhepatic disorders, we reviewed our experience between 1997 and 2000 at Hadassah University Hospital (Jerusalem, Israel). Controls were patients who were HBV carriers and who, between 1990 and 1995, were treated for hematological malignancies but were not treated with lamivudine. Eighteen HBsAg-positive patients were treated with immunosuppression. Fourteen were males, with a mean age of 48 years. Eleven patients had lymphoma; 2 had colonic adenocarcinoma; and 5 had cryoglobulinemia, enophthalmitis, vasculitis, malignant histocytosis, or ulcerative colitis. Fourteen patients were treated with chemotherapy, and 4 with prolonged high-dose corticosteroids. All patients were HBsAg-positive; 4 had hepatitis B e antigen, and 10 had HBV DNA by polymerase chain reaction. Lamivudine was administered to 13 patients in the treatment group 1 to 60 days (mean, 15 days) before immunosuppressive treatment and continued 0.5 to 24 months (mean, 7 months) following initiation of immunosuppression. Mean follow-up after lamivudine administration was 21 months. Three patients died of lymphoma complications and 10 (77%) survived. None of the patients had clinical or serological evidence of HBV reactivation during or after lamivudine prophylaxis. Of 6 patients who presented with liver function test disturbances, 5 improved during combined lamivudine and immunosuppression treatment. At the end of follow-up, HBV DNA became undetectable in 2 of 10 patients. In 2 patients, seroconversion from HBsAg to anti-HBs was observed. In contrast, 2 of 5 control patients had HBV reactivation. Lamivudine prophylaxis in HBsAg carriers receiving immunosuppressive therapy may prevent HBV reactivation and hepatic failure.

Abstract Purpose of Review While kidney transplantation improves the long-term survival of the majority of patients with end-stage kidney disease (ESKD), age-related immune dysfunction and associated comorbidities make older transplant recipients more susceptible to complications related to immunosuppression. In this review, we discuss appropriate management of immunosuppressive agents in older adults to minimize adverse events, avoid acute rejection, and maximize patient and graft survival. Recent Findings Physiological changes associated with senescence can impact drug metabolism and increase the risk of post-transplant infection and malignancy. Clinical trials assessing the safety and efficacy of immunosuppressive agents in older adults are lacking. Recent findings from U.S. transplant registry–based studies suggest that risk-adjusted death-censored graft failure is higher among older patients who received antimetabolite avoidance, mammalian target of rapamycin inhibitor (mTORi)–based, and cyclosporine-based regimens. Observational data suggest that risk-adjusted mortality may be increased in older patients who receive mTORi-based and cyclosporine-based regimens but lower in those managed with T cell induction and maintenance steroid avoidance/withdrawal. Summary Tailored immunosuppression management to improve patient and graft survival in older transplant recipients is an important goal of personalized medicine. Lower intensity immunosuppression, such as steroid-sparing regimens, appears beneficial whereas mTORi- and cyclosporine-based maintenance are associated with greater potential for adverse effects. Prospective clinical trials to assess the safety and efficacy of immunosuppression agents in older recipients are urgently needed.

Abstract Background Immunosuppressed patients such as kidney transplant recipients (KTs) have increased mortality risk in the setting of coronavirus disease 2019 (COVID-19). The role and management of chronic immunosuppressive therapies during COVID-19 must be characterized. Methods Herein, we report the follow-up of a cohort of 47 KTs admitted at two Spanish Kidney Transplant Units, who survived COVID-19. The impact of the management of immunosuppression during COVID-19 on graft function and immunologic events was evaluated. Results At least one immunosuppressive agent was withdrawn in 83% of patients, with antimetabolites being the most frequent. Steroids were generally not stopped and the dose was even increased in 15% of patients as part of the treatment of COVID-19. Although immunosuppressive drugs were suspended during a median time of 17 days, no rejection episodes or de novo donor-specific antibodies were observed up to 3 months after discharge, and no significant changes occurred in calculated panel reactive antibodies. Acute graft dysfunction was common (55%) and the severity was related to tacrolimus trough levels, which were higher in patients receiving antivirals. At the end of follow-up, all patients recovered baseline kidney function. Conclusions Our observational study suggests that immunosuppression in KTs hospitalized due to COVID-19 could be safely minimized.

BackgroundPharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants.MethodsIn a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation.ResultsIn the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µg/L, P<0.001) and cyclosporin A (47.4 versus 64.1 µg/L, P<0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation (P=0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events.ConclusionsSteering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs.Clinical Trial registry name and registration number:IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRCTN89806912

Transplantation is the only cure for end-stage organ failure. Current immunosuppressive drugs have two major limitations: 1) non antigen specificity, which increases the risk of cancer and infection diseases, and 2) chronic toxicity. Cell therapy appears to be an innovative and promising strategy to minimize the use of immunosuppression in transplantation and to improve long-term graft survival. Preclinical studies have shown efficacy and safety of using various suppressor cells, such as regulatory T cells, regulatory B cells and tolerogenic dendritic cells. Recent clinical trials using cellbased therapies in solid organ transplantation also hold out the promise of improving efficacy. In this review, we will briefly go over the rejection process, current immunosuppressive drugs, and the potential therapeutic use of regulatory cells in transplantation.

Myeloid-derived suppressor cells (MDSCs) expand during pathological conditions in both humans and mice and their presence is linked to poor clinical outcomes for cancer patients. Studying MDSC immunosuppression is restricted by MDSCs’ rarity, short lifespan, heterogeneity, poor viability after freezing and the lack of MDSC-specific markers. In this review, we will compare identification and isolation strategies for human and murine MDSCs. We will also assess what direct and indirect immunosuppressive mechanisms have been attributed to MDSCs. While some immunosuppressive mechanisms are well-documented in mice, e.g., generation of ROS, direct evidence is still lacking in humans. In future, bulk or single-cell genomics could elucidate which phenotypic and functional phenotypes MDSCs adopt in particular microenvironments and help to identify potential targets for therapy.

Resumo: A resposta imune na leishmaniose pode resultar em uma polarização da subpopulação dos linfócitos T, levando a um fenótipo celular distinto, que resultam em proteção imune ou exacerbação da doença. As leishmânias persistem no organismo tanto em infecções assintomáticas como após o tratamento, representando risco em condições de imunossupressão. O objetivo deste trabalho foi avaliar o efeito da infecção e da imunossupressão com dexametasona associada à pentoxifilina, sobre o peso dos animais, peso do baço, carga parasitária do baço e do fígado, e da imunopatologia quanto à produção de IFN-γ, IL-10, IL-4 e IL-2 em cultura de células esplênicas de camundongos Balb/c infectados com Leishmania chagasi. A infecção não alterou o ganho de peso dos animais, mas sim o peso e o tamanho do baço. A imunossupressão utilizando a dexametasona associada à pentoxifilina afetou tanto ganho de peso, quanto o peso e o tamanho do baço, de animais infectados e não infectados. A imunossupressão não alterou significativamente o curso da carga parasitária, tanto do baço, como do fígado. A dexametasona e a pentoxifilina afetaram a produção das citocinas estudadas, mas não direcionaram o perfil de resposta Th1/Th2 nos animais infectados.
Abstract: The immune response in leishmaniasis can result in a polarization of a subpopulation of T lymphocytes, leading to a different cell phenotype, resulting in immune protection or exacerbation of the disease. Leishmanias persist in the body both in asymptomatic infections and after the treatment, representing risk in terms of immunosuppression. The objective of this study was to evaluate the effect of infection and immunosuppression with dexamethasone associated with pentoxifylline on the weight of the animals, weight of the spleen, the parasitic load in the spleen and liver, and immunopathology on the production of IFN-γ, IL - 10, IL-4, and IL-2 in spleen cell culture of Balb/c mice infected with Leishmania chagasi. The infection did not alter the animals' weight gain, but the weight and size of the spleen increased. The immunosuppression using dexamethasone associated with pentoxifylline affected both weight gains, as the weight and size of the spleen of infected and not infected animals. The immunosuppression did not alter significantly the course of the parasite burden of the spleen and the liver. Dexamethasone and pentoxifylline affected the studied cytokines production, but not influenced the profile of Th1/Th2 response in infected animals.
Orientador: Helio Langoni
Coorientador: Luciane Alarcão Dias-Melício
Banca: Angela Maria Victoriano de Campos
Banca: Lisiane de Almeida Martins
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Orientador: Paulo César Ciarlini
Banca: Áureo Evangelista Santana
Banca: Aguemi Kohayagawa
Resumo: Embora a insuficiência renal ocorra com bastante freqüência na espécie canina, não se sabe se essa condição, a semelhança do que ocorre em humano, compromete o funcionamento dos poliformonucleares (PMN). O superóxido produzido pelo metabolismo oxidativo dos PMN exerce importante papel na resposta imune inata, destruído os patógenos fagocitados, entretanto, quando em excesso age de modo deletério promovendo a aceleração da apoptose. Testou-se a hipótese de que, a semelhança do que ocorrer em humanos, as toxinas presentes no soro de cães urêmicos alteram o metabolismo oxidativo e acelera a morte celular programada dos neutrófilos de cães normais. Para tal o sangue total e polimorfonucleares isolados de dez cães sadios foram incubados com soro urêmico. A produção de superóxido foi quantificada pelo teste de redução do tetrazólio nitroazul (NBT) e o índice apoptótico calculado pelo método morfométrico. A produção de superóxido gerada dos neutrófilos de sangue total tratados com soro urêmico apresentou significante redução (p < 0,05). Quando isolados e incubados com soro urêmico, apenas na metade das amostras os PMN apresentaram concomitantemente diminuição da produção de superóxido e aumento do índice apoptótico. Foi possível concluir que os componentes presentes no soro urêmico alteram ex vivo o metabolismo oxidativo e a apoptose dos PMN, fortalecendo a hipótese de que cães com de insuficiência renal têm sua imunidade inata comprometida.
Abstract: Although kidney failure occurs frequently on canine species, it is unknown if this condition, being similar to what occurs in human beings, jeopardized the functioning of the polymorphonuclear (PMN). The superoxide produced by the oxidative metabolism of the PMN plays an important role in the immune inherent answer, having destroyed the pathogenic phagocytized. However, when in excess it acts in a deleterious way promoting the acceleration of apoptosis. It was tested by the hypothesis that, similar to what occurs in humans, the toxins present in the serum of uremic dogs alter the oxidative metabolism and accelerates the programmed cellular death of the neutrophis of normal dogs. For that, the total blood and polymorphonuclears isolated from ten healthy dogs were incubated with uremic serum. The production of superoxide was quantified by nitroblue tetrazolium reduction test (NBT) and the index apoptic was calculated by the morphometric method. The production of superoxide generated from the neutrophil of total blood treated with uremic serum presented significant reduction (P<0.05). When isolated and incubated with uremic serum, only on half of the sample the PMN presented concomitantly a reduction of production of superoxide and increase of apoptotic index. It was possible deduct that the components present in the uremic serum alter ex vivo the oxidative metabolism and the apoptosis of the PMN, consolidating the hypothesis that dogs having kidney failure have their inherent immunity jeopardized.
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Orientador: Valdir Gouveia Garcia
Banca: Nivaldo Antonio Parizotto
Banca: Álvaro Francisco Bosco
Resumo: O processo de reparo de feridas em indivíduos imunossuprimidos pelo uso de medicação corticóide representa um problema para a área da saúde. Diversos tipos de tratamento têm sido propostos para se obter uma melhor qualidade no processo de reparo, dentre esses destaca-se o uso do laser em baixa intensidade e, mais recentemente, a terapia fotodinâmica (PDT), representada pela associação do laser com drogas fotossensibilizadoras, como o Azul de Toluidina O (TBO). O propósito deste trabalho foi avaliar, histologicamente, a ação do laser em baixa intensidade e da PDT no processso de reparo em feridas cutâneas em ratos tratados com corticóide. Foram utilizados 90 ratos, nos quais foi criada, com o auxílio de um punch, uma ferida de 8 mm de diâmetro na porção média da região dorsal. Os animais foram divididos em 5 grupos: grupo 1 (n=18): os animais não receberam nenhum tipo de tratamento, tanto local quanto sistêmico; grupo 2 (n=18): os animais receberam corticóide sistêmico e nenhum tratamento local; grupo 3 (n=18): os animais receberam sistemicamente o mesmo tratamento do grupo 2, sendo as feridas tratadas com laser de baixa intensidade; grupo 4 (n=18): os animais receberam o mesmo tratamento sistêmico do grupo 2, sendo as feridas tratadas com irrigação de TBO; e grupo 5 (n=18): os animais receberam o mesmo tratamento do grupo 4, sendo as feridas tratadas imediatamente após a sua execução, com laser em baixa intensidade. Os animais, em número de 06 (seis) para cada grupo, foram sacrificados nos períodos de 3, 7 e 14 dias após a execução dos procedimentos terapêuticos. As peças foram processadas para análise histológica e coradas pela técnica da hematoxilina e eosina (H&E) e Tricômico de Masson. Os resultados mostraram que o grupo 2 promoveu um retardo na reparação tecidual em todos os períodos experimentais... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The process of wounds repair in immunosuppressed individuals for the use of corticoid therapy represents a problem for the area of health. Several treatment types have been proposed to obtain a better quality in the repair process. Among those, the use of low level laser may be emphasized and, more recently, the photodynamic therapy (PDT), represented by the association of that laser with photosensibilized drugs like toluidine blue O (TBO). The aim of this study was to evaluate, histologically, the action of the laser and of PDT in the repair process in cutaneous wounds in rats treated with corticoid. Ninety rats were used, in which was created, with the aid of a punch of 8 mm diameter, a wound in the medium portion of the dorsal region. The animals were divided in 5 groups: group 1 (n=18): the animals didn't receive any treatment type, local or systemic; group 2 (n=18): the animals received systemic corticoid and any local treatment; group 3 (n=18): the animals received systemically the same treatment of the group 2, being the wounds treated with low level laser; group 4 (n=18): the animals received the same systemic treatment of groups 2, being the wounds treated with irrigation of TBO; and group 5 (n=18): the animals received the same treatment of the group 4, being the wounds immediately treated after their execution with laser. The animals, in number of 06 (six) for each group, were sacrificed in the periods of 3, 7 and 14 days after the execution of the therapeutic procedures. The pieces were processed for histologic analysis and colored for the technique of hematoxylin-eosin (H&E) and Masson trichrome stains. The results showed that the group 2 promoted a retard in the tissue repair in all the experimental periods; the group 3 presented a more accelerated repair process than the group 4, as well as the group 5 was presented... (Complete abstract click electronic access below)
Mestre

Orientador: Valdir Gouveia Garcia
Banca: Maria José Hitomi Nagata
Banca: Adriana Campos Passanezi Santana
Resumo: O objetivo deste estudo foi avaliar histológica e histometricamente a influência da terapia fotodinâmica (PDT) no tratamento da doença periodontal induzida em ratos tratados ou não com corticóide. Cento e oitenta ratos foram divididos em 2 grupos de 90 animais. Os do Grupo A sofreram aplicações subcutâneas de soro fisiológico e os do Grupo B, aplicações subcutâneas de corticóide. A doença periodontal foi induzida por ligadura e após 7 dias foi removida e os animais divididos em subgrupos que receberam os tratamentos: I - raspagem e alisamento radicular (RAR) e irrigação com soro fisiológico; II - RAR e irrigação com azul de toluidina O (TBO); III - tratamento similar ao do grupo II e, após 1 minuto, aplicação do laser de ArGaAl (660 nm, 4J), realizando a terapia fotodinâmica (PDT). Dez animais de cada subgrupo foram sacrificados aos 7, 15 e 30 dias. Os espécimes foram processados laboratorialmente para análises histológica e histométrica. O tratamento com RAR (Grupos A e B) mostrou, aos 7, 15 e 30 dias, elevado número de neutrófilos e crista óssea com trabéculas finas e desorganizadas comparado ao TBO e PDT. No grupo A, a perda óssea (PO) foi significativamente maior (p<0,05) no tratamento com RAR (1,12±0,13; 0,90±0,27; 1,00±0,16) que no TBO no período de 7 dias (0,67±0,14) e quando comparado ao PDT em todos os períodos experimentais (0,54±0,06; 0,56±0,13; 0,53±0,05). No grupo B, houve maior perda óssea no tratamento com RAR (1,65±0,15; 1,71±0,11; 1,5±0,25) em relação ao TBO (0,74±0,12; 1,06±0,10; 0,75±0,31) e PDT (0,60±0,10; 0,59±0,13; 0,57±0,10) em todos períodos avaliados. O tratamento com PDT apresentou PO significativamente menor (p<0,05) que com TBO (15 dias) nos grupos A e B. Animais do grupo B, tratados com a PDT, demonstraram menor PO comparados aos animais do Grupo A, tratados pela RAR, aos 7 e 15 dias.
Abstract: The purpose of this study was to evaluate histological and histometrically the influence of photodynamic therapy (PDT) in the treatment of periodontal disease induced in rats treated with corticosteroids or not. One hundred and eighty rats were divided into 2 groups of 90 animals. The Group's A suffered applications of subcutaneous saline in the Group B, subcutaneous application of corticosteroids. The periodontal disease was induced by ligation and after 7 days was removed and the animals divided into subgroups who received the treatments: I - scraping and hair root (RAR) and irrigation with saline; II - RAR, and irrigation with toluidine blue O ( TBO); III - treatment similar to the group II and, after 1 minute, ArGaAl of application of laser (660 nm, 4J), performing photodynamic therapy (PDT). December animals of each subgroup were sacrificed at 7, 15 and 30 days. The laboratory specimens were processed for histological analysis and histométrica. Treatment with RAR (Groups A and B) showed, at 7, 15 and 30 days, large numbers of neutrophils and crest bone trabeculae with fine and desorganizadas compared to TBO and PDT. In group A, bone loss (PP) was significantly higher (p <0.05) in treatment with RAR (1.12 ± 0.13, 0.90 ± 0.27, 1.00 ± 0.16), TBO in the period of 7 days (0.67 ± 0.14) and compared to PDT in all experimental periods (0.54 ± 0.06, 0.56 ± 0.13, 0.53 ± 0.05 ). In group B, there was greater bone loss in the treatment with RAR (1.65 ± 0.15, 1.71 ± 0.11, 1.5 ± 0.25) compared to TBO (0.74 ± 0.12; 1.06 ± 0.10, 0.75 ± 0.31) and PDT (0.60 ± 0.10, 0.59 ± 0.13, 0.57 ± 0.10) in all periods evaluated. Treatment with PDT presented PP significantly lower (p <0.05) than with TBO (15 days) in groups A and B.
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Orientador: Samir Issa Samara
Banca: Maria da Gloria Buzinaro
Banca: Fumio Honma Ito
Resumo: O presente trabalho teve como objetivo verificar a variação da ocorrência da Rinotraqueíte Infecciosa Bovina (IBR) pela associação com duas doenças virais imunossupressoras: a Diarréia Viral Bovina (BVD) e a Leucose Enzoótica Bovina (LEB), em seis propriedades onde não se adota esquema de vacinação contra essas enfermidades. Amostras de soro sangüíneo foram analisadas no teste de virusneutralização (VN), para constatação de IBR e BVD, e Imunodifusão em Gel de Ágar (IDGA), para a LEB. Foram selecionados cinco rebanhos bovinos, em propriedades localizadas em municípios dos Estados de São Paulo e Minas Gerais, sendo três de exploração leiteira, um de gado de corte e um misto, com animais soropositivos ao BoHV-1, além de um rebanho controle, sem anticorpos contra essa enfermidade. Das 278 amostras analisadas, 54,68% (152/278) foram positivas ao BoHV-1, 69,70% (194/278) ao BVDV-1 e 34,33% (96/278) ao VLEB. Na análise estatística, ao relacionar cada enfermidade com o tipo de exploração do rebanho e a idade dos animais, houve diferença significativa, indicando que estas variáveis são fatores de risco para as enfermidades estudadas. Em relação ao tipo de exploração, os rebanhos leiteiros foram mais suscetíveis ao BoHV-1 e a LEB (81,31% e 49,53% respectivamente, (α = 1 ) enquanto no rebanho de gado de corte o BVDV-1 teve maior ocorrência (94,74%, α = 1). A idade foi fator de risco apenas para o BoHV-1 e a LEB, sendo os animais mais velhos os mais suscetíveis (α = 1). As associações entre o BoHV-1 e o BVDV-1, e o BoHV-1 e a LEB também foram significativas (α = 5 e α = 1 respectivamente), indicando que em rebanhos infectados por BVDV-1 e/ou LEB, a probabilidade de se encontrar o BoHV-1 é maior do que naqueles onde não ocorre essas duas enfermidades.
Abstract: The present research had as objective to verify the variation of the occurrence of Infectious Bovine Rhinotracheitis (IBR) by association with two viral infections that affect the immune system, Bovine Viral Diarrhoea (BVD) and enzootic bovine leukosis (EBL), in six farms where vaccination against these diseases was not adopted. Serum samples had been analyzed by the virus neutralization (VN) test for IBR and BVD diagnosis, and agar gel immunodiffusion (IDGA) test for EBL diagnosis. Five cattle herds with BoHV-1 seropositive animals had been selected in the states of São Paulo and Minas Gerais, three of them exploiting dairy cattle, one exploiting beef cattle and one exploiting mixed cattle, in addition to a control herd without seropositive animals. From 278 analyzed samples, 54.68% (152/278) reacted to the BoHV-1, 69.70% (194/278) to the BVDV-1, and 34.33% (97/278) to the EBLV. The statistic analysis showed a significant difference (α = 1) in infection occurrence according to the kind of exploitation and the age of the animals. Dairy cattle were more sensitive to the BoHV-1 (81.31%) and to the EBLV (49.53%) and less to BVDV-1 infection (45.79%). Among the beef herds, the major occurrence was BVDV-1 infection (94.74%), followed by BoHV-1(34.19%) and EBLV (3.95%). The age was a risk factor (α = 1) only for BoHV-1 and EBLV. The associations between BoHV-1 and BVDV-1 infections (α = 5) and between BoHV-1 and EBLV infections (α = 1) also indicated that among BVDV-1 and/or EBLV infected herds the probability of finding BoHV-1 is higher than among herds where these two infections does not occur.
Mestre

PhD
Introduction Kidney transplantation confers both survival and quality of life advantages over dialysis for most people with end-stage kidney disease (ESKD). The mortality rate on dialysis is 10-15% per year, compared with 2-4% per year post-transplantation. Short-term graft survival is related to control of the acute rejection process, requiring on-going immunosuppression. Most current immunosuppressive algorithms include one of the calcineurin inhibitors (CNI: cyclosporin or tacrolimus), an anti-metabolite (azathioprine or mycophenolate) and corticosteroids, with or without antibody induction agents (Ab) given briefly peri-transplantation. Despite this approach, between 15-35% of recipients undergo treatment for an episode of acute rejection (AR) within one year of transplantation. Transplantation is not without risk, and relative mortality rates for kidney recipients after the first post-transplant year remain 4-6 times that of the general population. Longer-term transplant and recipient survival are related to control of chronic allograft nephropathy (rooted in the interplay of AR, non-immunological factors, and the chronic nephrotoxicity of CNI) and limitation of the complications of chronic ESKD and long-term immunosuppression: cardiovascular disease, cancer and infection, which are responsible for 22%, 39% and 21% of deaths respectively. This thesis is presented as published works on the theme of immunosuppression and cancer after kidney transplantation. The work presented in the first chapters of this thesis has striven to identify, evaluate, synthesise and distil the entirety of evidence available of new and established immunosuppressive drug agents through systematic review of randomised trial data, with particular emphasis on quantifying harms of treatment. The final chapters use inception cohort data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), which is first validated then used to explore the risk of cancer in more detail than was possible from trial data alone. Interleukin 2 receptor antagonists Interleukin-2 receptor antagonists (IL2Ra, commercially available as basiliximab and daclizumab) are humanised or chimeric IgG monoclonal antibodies to the alpha subunit of the IL2 receptor present only on activated T lymphocytes, and the rationale for their use has been as induction agents peri-transplantation. Introduced in the mid-1990s, IL2Ra use has increased globally, and by 2003 38% of new kidney transplant recipients in the United States and 25% in Australasia received an IL2Ra. This study aimed to systematically identify and synthesise the evidence of effects of IL2Ra as an addition to standard therapy, or as an alternative to other induction agents. We identified 117 reports from 38 randomised trials involving 4893 participants. Where IL2Ra were compared with placebo (17 trials; 2786 patients), graft loss was not different at one (Relative Risk -RR 0.84; 0.64 to 1.10) or 3 years (RR 1.08; 0.71 to1.64). AR was reduced at 6 months (RR 0.66; 0.59 to 0.74) and at 1 year (RR 0.66; 0.59 to 0.74) but cytomegalovirus (CMV) disease (RR 0.82; CI 0.65 to 1.03) and malignancy (RR 0.67; 0.33 to1.36) were not different. Where IL2Ra were compared with other antibody therapy no significant differences in treatment effects were demonstrated, but IL2Ra had significantly fewer side effects. Given a 40% risk of rejection, 7 patients would need treatment with IL2Ra in addition to standard therapy, to prevent 1 patient having rejection, with no definite improvement in graft or patient survival. There was no apparent difference between basiliximab and daclizumab. Tacrolimus versus cyclosporin for primary immunosuppression There are pronounced global differences in CNI use; 63% of new kidney transplant recipients in the USA but only 22% in Australia receive tacrolimus as part of the initial immunosuppressive regimen. The side effects of CNI differ: tacrolimus is associated more with diabetes and neurotoxicity, but less with hypertension and dyslipidaemia than cyclosporin, with uncertainty about equivalence of nephrotoxicity or how these relate to patient and graft survival, or impact on patient compliance and quality of life. This study aimed to systematically review and synthesise the positive and negative effects of tacrolimus and cyclosporin as initial therapy for renal transplant recipients. We identified 123 reports from 30 randomised trials involving 4102 participants. At 6 months graft loss was reduced in tacrolimus-treated recipients (RR 0•56; 0•36 to 0•86), and this effect persisted for 3 years. The relative reduction in graft loss with tacrolimus diminished with higher levels of tacrolimus (P=0.04), but did not vary with cyclosporin formulation (P=0.97) or cyclosporin level (P=0.38). At 1 year, tacrolimus patients suffered less AR (RR 0•69; 0•60 to 0•79), and less steroid-resistant AR (RR 0•49; 0•37 to 0•64), but more insulin-requiring diabetes (RR 1•86; 1•11 to 3•09), tremor, headache, diarrhoea, dyspepsia and vomiting. The relative excess in diabetes increased with higher levels of tacrolimus (P=0.003). Cyclosporin-treated recipients experienced significantly more constipation and cosmetic side-effects. We demonstrated no differences in infection or malignancy. Treating 100 recipients with tacrolimus instead of cyclosporin for the 1st year post-transplantation avoids 12 suffering acute rejection and 2 losing their graft but causes an extra 5 to become insulin dependent diabetics, thus optimal drug choice may vary among patients. Target of rapamycin inhibitors for primary immunosuppression Target of rapamycin inhibitors (TOR-I) are among the newest immunosuppressive agents and have a novel mode of action but uncertain clinical role. Sirolimus is a macrocyclic lactone antibiotic and everolimus is a derivative of sirolimus. Both prevent DNA synthesis resulting in arrest of the cell cycle. Animal models suggested TOR-I would provide synergistic immunosuppression when combined with CNI, but early clinical studies demonstrated synergistic nephrotoxicity. Since then diverse trials have explored strategies that avoid this interaction and investigated other potential benefits. The aim of this study was to systematically identify and synthesise available evidence of sirolimus and everolimus when used in initial immunosuppressive regimens for kidney recipients. We identified 142 reports from 33 randomised trials involving 7114 participants, with TOR-I evaluated in four different primary immunosuppressive algorithms: as replacement for CNI, as replacement for antimetabolites, in combination with CNI at low and high dose, and with variable dose of CNI. When TOR-I replaced CNI (8 trials, 750 participants), there was no difference in AR (RR 1.03; 0.74 to 1.44), but creatinine was lower (WMD -18.31 umol/l; -30.96 to -5.67), and bone marrow more suppressed (leucopoenia RR 2.02; 1.12 to 3.66, thrombocytopenia RR 6.97; 2.97 to 16.36, anaemia RR 1.67; 1.27 to 2.20). When TOR-I replaced antimetabolites (11 trials, 3966 participants), AR and CMV were reduced (RR 0.84; 0.71 to 0.99 and RR 0.49; 0.37 to 0.65) but hypercholesterolaemia was increased (RR 1.65; 1.32 to 2.06). When low was compared to high-dose TOR-I, with equal CNI dose (10 trials, 3175 participants), AR was increased (RR 1.23; 1.06 to 1.43) but GFR higher (WMD 4.27 ml/min; 1.12 to 7.41). When low-dose TOR-I and standard-dose CNI were compared to higher-dose TOR-I and reduced CNI AR was reduced (RR 0.67; 0.52 to 0.88), but GFR also reduced (WMD -9.46 ml/min; -12.16 to -6.76). There was no significant difference in mortality, graft loss or malignancy risk demonstrated for TOR-I in any comparison. Generally surrogate endpoints for graft survival favoured TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes were worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust randomised trials are still needed. Monoclonal and polyclonal antibody therapy for treating acute rejection Strategies for treating AR include pulsed steroids, an antibody (Ab) preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the USA 61.4% of patients with AR received steroids, 20.4% received Ab and 18.2% received both. The Ab available for AR are not new: horse and rabbit derived polyclonal antibodies (ATG and ALG) have been used for 35 years, and a mouse monoclonal antibody (muromonab-CD3) became available in the late 1980s. These preparations remove the functional T-cell population from circulation, producing powerful saturation immunosuppression which is useful for AR but which may be complicated by immediate toxicity and higher rates of infection and malignancy. The aim of this study was to systematically evaluate and synthesise all evidence available to clinicians for treating AR in kidney recipients. We identified 49 reports from 21 randomised trials involving 1394 participants. Outcome measures were inconsistent and incompletely defined across trials. Fourteen trials (965 patients) compared therapies for 1st AR episodes (8 Ab versus steroid, 2 Ab versus another Ab, 4 other comparisons). In treating first rejection, Ab was better than steroid in reversing AR (RR 0.57; CI 0.38 to 0.87) and preventing graft loss (RR 0.74; CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection (RR 0.67; CI 0.43 to 1.04) or death (RR 1.16; CI 0.57 to 2.33) at 1 year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection (4 Ab vs another Ab, 1 different doses Ab, 1 different formulation Ab, 2 other comparisons). There was no benefit of muromonab-CD3 over ATG or ALG in reversing rejection (RR 1.32; CI 0.33 to 5.28), preventing subsequent rejection (RR 0.99; CI 0.61 to 1.59), graft loss (RR 1.80; CI 0.29 to 11.23) or death (RR 0.39; CI 0.09 to 1.65). Given the clinical problem caused by AR, comparable data are sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed. Validity of cancer data in an end stage kidney disease registry Registries vary in whether the data they collect are given voluntarily or as a requirement of law, the completeness of population coverage, the breadth of data collected and whether data are assembled directly or indirectly through linkage to other databases. Data quality is crucial but difficult to measure objectively. Formal audit of ANZDATA cancer records has not previously taken place. The aim of this study was to assess agreement of records of incident cancer diagnoses held in ANZDATA (voluntary reporting system) with those reported under statute to the New South Wales (NSW) state Central Cancer Registry (CCR), to explore the strengths and weaknesses of both reporting systems, and to measure the impact of any disagreement on results of cancer analyses. From 1980-2001, 9453 residents received dialysis or transplantation in NSW. Records from ANZDATA registrants were linked to CCR using probabilistic matching and agreement between registries for patients with 1 or more cancers, all cancers and site-specific cancer was estimated using the kappa-statistic (κ). ANZDATA recorded 867 cancers in 779 (8.2%) registrants; CCR 867 cancers in 788 (8.3%), with κ =0.76. ANZDATA had sensitivity 77.3% (CI 74.2 to 80.2), specificity 98.1% (CI 97.7 to 98.3) if CCR records were regarded as the reference standard. Agreement was similar for diagnoses whilst receiving dialysis (κ =0.78) or after transplantation (κ =0.79), but varied by cancer type. Melanoma (κ =0.61) and myeloma (κ =0.47) were less good; lymphoma (κ =0.80), leukaemia (κ =0.86) and breast cancer (κ =0.85) were very good. Artefact accounted for 20.8% non-concordance but error and misclassification did occur in both registries. Cancer risk did not differ in any important way whether estimated using ANZDATA or CCR records. Quality of cancer records in ANZDATA are high, differences largely explicable, and seem unlikely to alter results of analyses. Risk of cancer after kidney transplantation Existing data on the magnitude of excess risk of cancer across different kidney recipient groups are sparse. Quantifying an individual transplant candidate’s cancer risk informs both pre-transplant counselling, treatment decisions and has implications for monitoring, screening and follow-up after transplantation. The aims of this study were firstly to establish the risk of cancer in the post-transplant population compared to that experienced by the general population, and secondly to quantify how excess risk varied within the transplanted population, seeking to establish meaningful absolute risk estimates for post-transplant cancer based on unalterable recipient characteristics known a priori at the time of transplantation. 15,183 residents of Australia and New Zealand had a transplant between 1963 and 2004, and were followed for a median of 7.2 years (130,186 person-years), with 1642 (10.8%) developing cancer. Overall, kidney recipients had 3 times the cancer risk, with risk inversely related to age (Standardised Incidence Ratio of 15 to 30 in children reducing to 2 in people > 65 years). Female recipients aged 25 -29 had rates of cancer (779.2/100,000) equivalent to women aged 55 - 59 from the general population. The risk pattern of lymphoma, colorectal and breast cancer was similar to the overall age trend, melanoma showed less variability across ages and prostate cancer showed no risk increase. Within the transplanted population cancer risk was affected by age differently for each sex (P=0.007), and was elevated for recipients with prior non-skin malignancy (Hazard Ratio: HR 1.40; 1.03 to 1.89), of white race (HR 1.36; 1.12 to 1.89), but reduced for those with diabetic ESKD (HR 0.67; 0.50 to 0.89) Rates of cancer in kidney recipients were similar to non-transplanted people 20 -30 years older, but risk differed across patient groups. Men aged 45 - 54 at transplantation with graft function at 10 years had a risk of cancer that varied from 1 in 13 (non-white, diabetic ESKD, no prior cancer) to 1 in 5 (white, prior cancer, ESKD from other causes).

Thesis (Ph. D.)--University of Sydney, 2006.
Title from title screen (viewed 21 May 2007). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Public Health, Faculty of Medicine. Includes bibliographical references. Also available in print form.

Introduction: NKT cells are categorised as borderline between NK and T cells, sharing phenotypic and functional characteristics of both cells, demonstrating their capacity to contritube to both pro- or anti-inflammatory processes. However, the role of these cells among lung transplant recipients remains largely unknown. The aim of this study was to determine the role of NKT cells following lung transplantation. Methods: NKT cells were quantified and characterised according to markers of: activation (CD107a, CD161, NKG2D) and immunomodulation (CD200 and CD200R) in peripheral blood and BALs. NKT cell numbers and phenotypes were correlated to clinical variables: immunosuppression, acute rejection, acute infections (viral, bacterial and fungal), bronchiolitis obliterans syndrome (BOS grade), lung function, and demographic variables. Interactions between NKT cells and the transplanted lung were linked by determining the relative expression of immunomodulatory ligand CD200 in lung biopsies. In vitro models were employed to determine the role of NKT cells to acute lung injury, either alone or in combination with cells of the mononuclear phagocyte system (MPS). Results: Higher numbers of immunomodulatory NKT cells (CD200+ and CD200R+) were found as lung function decreased. Data from peripheral blood indicates that recipients whose donors or themselves had been exposed to CMV infection demonstrated increased numbers of NKT cells. Patients with active EBV infections demonstrated higher NKT cell numbers expressing CD200 and CD200R. Data from BALs, indicates that patients with active fungal infections present higher immunomodulatory (CD200R) NKT cells and lower cytotoxicity marker (CD107a). In peripheral blood, lung recipients demonstrated higher NKT cell numbers compared to healthy volunteers. However, the lower relative mean expression of functional markers in the lung transplant group suggests that cells are less active. In vitro cultures with immunosuppressants demonstrated that cell cycle inhibitors (MMF and AZA) and corticosteroids (Prednisolone) are likely to inhibit NKT cell proliferation, while calcineurin inhibitors (Cyclosporine A and Tacrolimus) decrease the relative mean expression of activation markers. Clinical observations indicate that higher doses of Azathioprine may correlate with increased NKT cell numbers and the relative expression of CD200 and CD200R. However, under these conditions the relative expression of activation marker NKG2D decreases. In vitro data from the acute injury model indicates that NKT cells are capable to migrate into the injured lung and become activated following transmigration which is facilitated by the presence of monocytes. We also observed the interaction of NKT cells with endothelial cells, monocytes and macrophages. Also, the relative mean expression of CD200 and CD200R increased at the capillary layer, regardless of injury while upregulation of activation markers (CD107a, CD161 and NKG2D) was found at the capillary layer, following injury. In contrast, the alveolar layer demonstrated a decrease in both activation and immunomodulatory markers, following acute injury. Conclusions: Despite immunosuppression, NKT cells remain present in peripheral blood and BAL following lung transplantation. NKT cell proliferation is likely to be reduced by effect of cell cycle inhibitors, while calcineurin inhibitors exert an immunomodulatory effect. Our data indicates that NKT cells can participate in inflammatory and immunomodulatory events at the alveolar bilayer. Their capacity to infiltrate the lungs was assisted by cells of the mononuclear phagocyte system (MPS), which play an important role in antigen presentation and modulation of acute injury. Further research is needed to elucidate the signals and mechanisms occurring between NKT and MPS interactions and the outcomes these populations drive in acute lung injury.

Aims: To explore the clinical significance of EBV infection in adult renal transplant recipients when detected in the late post-transplant period. Methods: (1) A prospective observational study recruiting 499 stable adult kidney transplant recipients with serial blood sampling for EBV DNAemia and assessment of clinical outcomes and associated factors. (2) A retrospective analysis of PTLD incidence, timing and outcomes in relation to EBV infection. Results: EBV DNAemia in stable kidney transplant recipients is common, found in 46% of recruited individuals screened over 1 year, with persistent DNAemia seen in 10%. DNAemia prevalence increased significantly with time from transplant (p<0.0001) from 16% within 1 year of transplant to 66% in those transplanted for 20-24 years. High baseline DNA levels predicted persistence of DNAemia. Time adjusted analyses showed significant association of DNAemia with EBV seronegative status and previous PTLD and low DNAemia rates with Mycophenolate Mofetil (MMF) use and lymphopenia. The mechanism did not appear to be directly linked to MMF induced B cell depletion. Chronic high viral load detection was significantly associated with time from transplant, EBV seronegative status at transplant, ciclosporin use and plasma detection of DNA. No significant differences in overall patient survival at 3 years, clinical symptoms or clinical findings such as anaemia, thrombocytopenia or rate of decline in renal function were seen between stable transplant recipients with and without EBV DNAemia. PTLD incidence also increases with time from transplant and was greatest during the 10th-14th post-transplant years. Disease was EBV positive in 68% cases. No statistically significant differences in overall patient survival, or overall disease complete response rates were seen in relation to recipient EBV serostatus or EBV status of PTLD histology. Conclusions: EBV DNAemia prevalence increases with time from transplant but was not associated with worse patient or graft survival or specific symptoms. PTLD incidence including EBV negative disease also increases with time from transplant but response rates and survival were not influenced by EBV serostatus or histological status.

Osobe kojima su transplantirani organi imaju povećan rizik pojave malignih oboljenja, među kojima dominiraju maligni tumori kože. Smatra se da je osnovni razlog primena imunosupresivne terapije, ali još nije sasvim jasan mehanizam i nivo dejstva različitih imunosupresiva. Važan uticaj na nastanak većine malignih tumora kože ima ultraljubičasto (UV) zračenje koje izaziva pojačano starenje kože u vidu histološki prepoznatljivog fotooštećenja, sa odlikama razvoja elastoze i limfocitne infiltracije. U našoj zemlji do sada nisu sprovođena istraživanja rizika pojave maligniteta kože kod transplantiranih pacijenata, ne postoje podaci o njihovoj incidenci, uticaju imunosupresivne terapije i drugim potencijalnim faktorima rizika. U dostupnoj literaturi nema objavljenih radova iz oblasti analize histološkog fotooštećenja kože kod osoba na imunosupresivnoj terapiji. Ciljevi ove studije preseka bili su utvrđivanje učestalosti, vrste i lokalizacije premalignih i malignih lezija kože kod pacijenata nakon transplantacije bubrega, povezanosti njihove pojave sa dužinom, vrstom i režimom primene imunosupresivne terapije i sa histološki verifikovanim fotooštećenjem perilezionalne kože. U studiju je uključeno 66 pacijenata kojima je transplantiran bubreg (primaoci organskog transplantata – POT). Relevantni podaci su prikupljeni putem upitnika i iz medicinske dokumentacije, kliničko-dermoskopskim pregledom kože uočene suspektne lezije su bioptirane u cilju postavljanja dijagnoze i utvrđivanja histoloških parametara fotooštećenja, a u studiju su uključeni i maligni tumori kože POT ispitanika uklonjeni u periodu od prethodnih 5 godina ali nakon transplantacije. Radi komparacije prisutnih faktora rizika i stepena fotooštećenja kože sa opštom populacijom formirana je kontrolna grupa (KG) ispitanika kojima je prethodno bioptirana koža, bez oboljenja bubrega i bez imunosupresije, slična po polu i životnoj dobi sa onim POT ispitanicima kojima je urađena biopsija. Za svaku leziju iz POT grupe obezbeđene su po 2 lezije iz KG, tako da je pojedinim ispitanicima POT grupe analizirano više lezija, dok je u KG 1 ispitanik – 1 lezija. Osnovno oboljenje bubrega do započinjanja dijalize kod ispitanika POT grupe prosečno je trajalo 7,67 godina, u strukturi oboljenja bubrega dominirao je hronični glomerulonefritis sa 31,8%, a ispitanici su na dijalizi bili prosečno 4,54 godine. Prosečna životna dob ispitanika u momentu transplantacije iznosila je 42,5 godina, 60,6% imalo je isključivo kadaveričnu transplantaciju, a prosečno trajanje jatrogene imunosupresije iznosilo je 4,89 god. U POT grupi bioptirane su 33 lezije, među kojima su od značaja za studiju bile 2 (6,1%) aktinične keratoze (AK), 3 (9,1%) displastična nevusa (DN), 1 (3,0%) melanom (MM), 3 (9,1%) skvamocelularna karcinoma (SCK) i 6 (18,2%) bazocelularnih karcinoma (BCK). U POT grupi učestalost MM bila je 1,5%, učestalost SCK 4,5%, učestalost BCK 9,1%, dok je utvrđeni relativan rizik pojave MM u POT populaciji 227 puta veći, BCK 316 puta veći, a SCK 805 puta veći nego u opštoj populaciji. Relativan rizik nastanka AK i DN nije određen zbog izostanka zvanične registracije u opštoj populaciji. POT grupa i KG nisu se statistički značajno razlikovale po Ficpatrikovom fototipu kože, profesionalnoj izloženosti UV zračenju, upotrebi solarijuma, broju solarnih opekotina, ličnoj anamnezi malignih tumora kože i konzumiranju cigareta. Pripadnici KG su se značajno više rekreativno izlagali UV zračenju, češće koristili sredstva za zaštitu od sunčevog zračenja, češće imali bliske srodnike sa malignim tumorima kože, češće konzumirali alkohol, značajno veći broj ispitanika KG imao je pregled kompletne kože i informaciju o merama prevencije od strane lekara, dok 50% ispitanika POT grupe nije znalo da su pod povećanim rizikom pojave maligniteta kože. U stepenu elastoze među grupama nije postojala statistički značajna razlika, dok je limfocitna infiltracija bila marginalno izrazitija u POT grupi bez obzira na vrstu lezije. U POT grupi utvrđena je statistički značajna povezanost prisustva malignog tumora sa većim stepenom perilezionalne limfocitne infiltracije i elastoze. U KG utvrđena je statistički značajna povezanost prisustva malignog tumora sa većim stepenom limfocitne infiltracije, dok nije bilo statistički značajne razlike u stepenu perilezionalne elastoze. U studiji je utvrđeno da osobe nakon transplantacije bubrega imaju statistički značajno veći rizik nastanka BCK, SCK i MM kože u odnosu na opštu populaciju, sa najčešćom lokalizacijom ovih tumora u predelu glave. Dužina primene imunosupresivne terapije uopšteno nije statistički značajno uticala na pojavu premalignih i malignih tumora kože, ali je kumulativna doza pojedinih imunosupresiva poput ciklosporina i azatioprina imala statistički značajan uticaj na pojavu premalignih i malignih lezija kože. Dužina imunosupresije je statistički značajno uticala na stepen elastoze, ali je imala marginalan uticaj na stepen perilezionalne limfocitne infiltracije.
Organ transplant recipients are at an increased risk of developing malignancies, with the predominance of malignant skin tumors. The main cause is considered to be the administration of immunosuppressive therapy, but the mechanism and effect levels of different immunosuppressive agents are still not completely clear. Ultraviolet (UV) rays also influence the development of malignant skin tumors, causing increased skin aging with histologically recognisable photo damage, with its hallmark being development of elastosis and lymphocytic infiltration. No research on the topic of risks of malignant skin tumors in transplant patients has been done in our country, there is no data on their incidence, or on the effects of immunosuppressive agents and other potential risk factors. There are also no published studies in the field of hystological photo damage analysis in patients on immunosuppressive therapy. The aims of this study were to establish the rates of occurance, types and localisation of premalignant and malignant skin lesions in kidney transplant recipients (KTR) and to associate their advent with the length, type and regimen of immunosuppressive therapy. A total of 66 KTR patients were enrolled in the study. Relevant information was gathered through a specially constructed questionnaire and from the medical records, followed by combined clinical and dermoscopic skin examination to detect suspicious lesions which were biopsied in order to determine the histopathologic diagnosis of the lesion and perilesional degree of photo damage. The study also encompassed malignant skin tumors of KTR patients that have been removed in the last 5 years, but after the transplantation. For the sake of comparison of the risk factors and the levels of photo damage with the general population, an age and sex - matched control group (CG) of patients with previous skin biopsy but without kidney disease and immunosuppression was formed. For each lesion from KTR group, 2 lesions from CG were provided, meaning that some KTR patients had several lesions analysed, whereas in the CG only 1 lesion per patient was analyzed. The average duration of underlying kidney diseases in KTR was 7,67 years, the most frequent being chronic glomerulonephritis (31,8%), and an average duration of dialysis was 4,54 years. The mean age at transplantation was 42,5 years, with 60,6% of the KTR having exclusively cadaveric graft. The mean duration of the iatrogenic immunosuppression was 4,89 years. In the KTR group a total of 33 lesions were biopsied, 2 of which were actinic keratoses (AK) (6,1%), 3 were dysplastic nevi (DN) (9,1%), 1 melanoma (MM) (3,0%), 3 squamous cell carcinomas (SCC) (9,1%) and 6 basal cell carcinomas (BCC) (18,2%). The estimated frequency of MM was 1,5%, SCC 4,5%, BCC 9,1%, and the estimated relative risk of MM in KTR being 227, BCC 316, and SCC 805 times higher compared to the general population. The relative risk of AK and DN development could not have been estimated as there are no official records in the general population. The KTR and CG were not significantly different judging by the Fitzpatrick skin phototype, occupational UV exposure, sunbed usage, personal history of skin cancers, or smoking. The controls were recreationally more exposed to UV rays, used sun protective measures more frequently, had more relatives with skin cancers and consumed alcohol more frequently. A significantly greater number of controls had had complete skin examination and protective measures counceling by the doctor, while 50% of KTR patients did not even know that they were at an increased risk of malignant skin tumor development. There was no significant difference in elastosis levels among the groups, whereas the lymphocitic infiltration was only marginally greater in the KTR group. A significant association between the level of perilesional photodamage and developement of malignant tumors was estimated for the KTR group, whereas in the CG only the perilesional lymphocitic infiltration was strongly associated to malignant lesions. The study results suggest that KTR patients have a significantly higher risk of BCC, SCC and MM development in comparison with the general population, the most common localisation being in the head region. The duration of the immunosuppressive therapy had no significant effect on the premalignant and malignant tumors development, whereas the cummulative dose of certain immunosuppressives (such as cyclosporine and azathioprine) affected the development notably. The duration of immunosuppression statistically influenced the elastosis levels, but had only a marginal influence on the perilesional lymphocitic infiltration levels.

Combination immunosuppressive therapy produces excellent short-term results after kidney transplantation. Long-term graft survival has improved, but less dramatically. Death with a functioning graft remains the primary cause of graft loss. Dosing of current immunosuppressive therapy balances between careful clinical interpretation of time-driven immunological risk assessments and drug-related toxicity on the one hand, and the use of simple surrogate drug exposure indicators like blood/plasma concentrations on the other. The combined use of calcineurin-inhibitors (CNIs) with mycophenolic acids and corticosteroids has been fine-tuned over the last decade, based on empirically derived observations as well as on the results of large multicentre randomized clinical studies. Corticosteroid withdrawal and avoidance are feasible, at least in patients with a low immunological risk, but CNI-free protocols have had few long-term successes. Some minimization strategies have increased risk of developing acute rejection or (donor-specific) anti-HLA antibodies, with deleterious effects on the graft. Mammalian target of rapamycin inhibitors (mTORi) have shown limited benefit in early CNI replacement regimens and their long-term use as primary drug is hampered by intolerance. In the setting of particular malignant disease occurring after transplantation, such as squamous cell carcinoma of the skin and Kaposi’s sarcoma, mTORi seem promising. Induction agents (anti-interleukin 2 receptor monoclonal antibodies, antithymocyte globulins) effectively diminish the risk of early immunological graft loss in recipients with moderate to high immunological risk but at the price of more infectious or malignant complications. While personalized transplantation medicine is only in its early stages of development, attempts are made to quantitatively measure the clinical degree of immunosuppression, to tailor immunosuppressive therapy more specifically to the patient’s individual profile, and to monitor graft status by use of invasive (e.g. surveillance renal biopsies) and non-invasive biomarkers. These scientific endeavours are a necessity to further optimize the current immunosuppressive therapy which will remain for some time to come.

Extra-muscular complications affecting patients suffering from the idiopathic inflammatory myopathies (IIM) are common, and appear in recognizable patterns affecting the skin, lungs, joints, oesophagus or heart, although these complications rarely all occur simultaneously. During the initial presentation of symptoms, involvement of organs other than muscle can aid the confirmation of the correct IIM subtype. Extra-muscular manifestations can be severe and life-threatening, e.g. with respiratory or cardiac involvement. Escalations of immunosuppression and other treatment modalities will likely be required in such cases since standard immunosuppression usually is not sufficient for an effective treatment of e.g. interstitial lung disease. IIM patients should therefore be regularly checked for extra-muscular manifestations, and management altered as appropriate.

End-organ disease has become a major cause of morbidity and mortality in HIV-infected patients due to increased life expectancy, increasing the demand for organ transplantation in these patients. The care of HIV-infected transplant recipients warrants a multidisciplinary team approach, including the transplant team, pharmacists, infectious disease specialists, nurses, and patients and their families. The immunosuppression of HIV-infected recipients post-transplant does not appear to further advance HIV disease. The post-transplant risk for HIV-infected recipients of opportunistic infections does not appear to be increased by immunosuppression. However, the overall rate of infections is high, and it is even higher in hepatitis C virus (HCV) co-infected transplant recipients. HIV/HCV co-infected recipients have worse outcomes compared to both liver and kidney HIV-infected recipients.

•Define the host: Identify factors that influence the type of infection, disease progression, and prognosis, which include:• Host factors such as patient age, immune status (eg, immunosuppression or the absence of a spleen), the presence of foreign bodies (eg, central venous catheter, permanent pacemaker, intracardiac defibrillator, prosthetic heart valves, prosthetic joints), or other comorbid conditions, ...

Since the start of the international project in 1997, over 1500 patients have received a haematopoietic stem cell transplant (HSCT), mostly autologous, as treatment for a severe autoimmune disease, with overall 85% 5-year survival and 43% progression-free survival. Around 30% of patients in all disease subgroups had a complete response, often durable despite full immune reconstitution. In many cases, e.g. systemic sclerosis, morphological improvement such as reduction of skin collagen and normalization of microvasculature was documented, beyond any predicted known effects of intense immunosuppression alone. It is hoped that the results of the three running large prospective randomized controlled trials will allow modification of the protocols to reduce the high transplant-related mortality which relates to regimen intensity, age of patient, and comorbidity. Multipotent mesenchymal stromal cells (MSC) have been recently tested in various autoimmune diseases, exploiting their immune modulating properties and apparent low acute toxicity. MSC display immune privilege in that the patient requires no immunosuppression prior to allogeneic MSC infusion. Despite encouraging small phase I/II studies, no positive data from randomized prospective studies are as yet available in the peer-reviewed literature.

Since the start of the international project in 1997, over 2000 patients have received a haematopoietic stem cell transplant (HSCT), mostly autologous, as treatment for a severe autoimmune disease, with overall 85% 5-year survival and 43% progression-free survival. Around 30% of patients in all disease subgroups had a complete response, often durable despite full immune reconstitution. In many cases, e.g. systemic sclerosis, morphological improvement such as reduction of skin collagen and normalization of microvasculature was documented, beyond any predicted known effects of intense immunosuppression alone. It is hoped that the results of the three running large prospective randomized controlled trials will allow modification of the protocols to reduce the high transplant-related mortality which relates to regimen intensity, age of patient, and comorbidity. Multipotent mesenchymal stromal cells (MSC) have been recently tested in various autoimmune diseases, exploiting their immune modulating properties and apparent low acute toxicity. MSC display immune privilege in that the patient requires no immunosuppression prior to allogeneic MSC infusion. Despite encouraging many small phase I/II studies, only 2 prospective controlled trials which achieved their primary endpoints have been published.

The clinical challenges arising when a person with a severe mental illness, such as schizophrenia or bipolar disorder, develops a cancer are surveyed. Delayed diagnosis and access to oncological treatment, factors contributing to reduced adherence, and the interruption of specialist community psychiatric care are discussed. Long-term psychotropic medication may complicate end-of-life care, and access to palliative care is usually limited for those in secure mental health inpatient units. The striking inverse relationship between neurodegenerative disorders (Alzheimer-type dementia) and proliferative disorders (cancers) is considered.Psychiatric aspects of haematopoietic stem cell transplantation (HSCT) are reviewed, including psychopathology arising from drugs used to prevent graft-versus-host disease and from infections complicating chronic immunosuppression. Cognitive impairment and suicide after HSCT are considered.

Renal transplantation is the preferred treatment for pediatric patients who have end-stage renal disease. A successful transplant improves intellectual and behavioral development, quality of life, and survival, with the survival at 10 years being as high as 83% (Kim et al., 1991). We can optimize the chance of success by understanding the pathophysiology involved and applying this knowledge to guide our management of perioperative fluid balance, electrolyte anomalies, anemia, blood pressure control, and comorbidities. Also critical is an appreciation of the effects and consequences of the various immunosuppressive agents that are used. Close communication is required between the pediatrician, surgeon, and anesthesiologist.

Congestive heart failure affects 23 million people worldwide [1]. Cardiac transplantation provides a lifesaving treatment for patients with end-stage heart disease. It offers a longer life with a higher quality to those who have no other treatment alternative. Although cardiac transplantation offers a relief from heart immunosuppression. The goal of immunosuppression immediately following surgery is to prevent hyperacute and acute rejections. Transplantation immunosuppression must be balanced in order to prevent rejection while minimizing the serious adverse effects of therapy including life-threatening infections and malignancies. Immunosuppressive regimens are classified as induction, maintenance, or anti-rejection regimens. Induction regimens consist of intense early post-operative immunosuppression while maintenance regimens are used indefinitely for prevention of acute and chronic rejection. This chapter will review the induction and maintenance immunosuppressive regimens used in heart transplantation with summaries of selected literature as well as the most common complications of these therapies and significant drug-drug interactions.

An understanding of the main aspects and functions of the immune system is important, i.e. physical barriers, innate, humoral, and cell-mediated immunity (see Chapter 6, Basic Immunology), when caring for the immunocompromised patient. In adults, secondary immunodeficiency is much more common than primary, and is most often due to iatrogenic immunosuppression with drugs, e.g. corticosteroids, chemotherapy agents, immunosuppressive agents, ‘biological’ therapies. For example, treatment with corticosteroids for more than one month is enough to increase the risk of some fungal infections such as Candida and Pneumocystis jirovecii, such that PCP prophylaxis should be considered in patients receiving ≤ 20mg/day prednisolone for four or more weeks. Chemotherapy and immunosuppressive agents may cause profound immunosuppression. The degree and duration of immunosuppression following a transplant, and the conditioning regimen used before the transplant varies with respect to the type of transplant: heart and lung transplant recipients typically receive more significant immunosuppression, and so are at increased risk of opportunistic infection compared to other solid-organ transplant recipients. Infections (e.g. HIV), cancer, and autoimmune disorders and the treatment of these conditions can also affect the immune system. Other diseases are also considered immunosuppressive although the exact nature of this is less well defined, for example, poorly controlled diabetes mellitus increases the risk of candidal infections and common bacterial infections. Cirrhosis is also considered to be a relatively immunosuppressed state. Understanding the nature of immune defects in both primary and secondary immunodeficiency allows more accurate prediction of overall infection risk and risk of specific pathogens, allowing a rational approach to infection prevention and investigation when patients become unwell. The initial assessment of the immunocompromised host should be to identify why the patient is immunocompromised, how long they have been immunocompromised (is it a congenital or acquired immunodeficiency?), and whether there is potential for immune recovery. Clearly, a person with a congenital immunodeficiency will have lifelong susceptibility to specific infections, unlike an acquired deficiency due to chemotherapy or transplantation which may be transient. If the immunosuppression is due to a drug, is it possible to reduce or change the immunosuppression? If an infection is suspected, pre-immunosuppression infection screening results can help identify whether the current presentation represents reactivation of a latent infection or primary infection.

With the dramatic progress of medical imaging modalities and growing needs for high-resolution intraoperative imaging in minimally invasive surgery, hybrid operative room (OR) has been developed as a powerful tool for different surgical scenarios. Under the guidance of high-definition cone beam CT (CBCT), an electromagnetic navigation bronchoscopy (ENB)-based marker implantation and subsequent localization of the pulmonary nodules can be implemented within a hybrid OR. Furthermore, the unparalleled real-time imaging capabilities and the ability to perform multiple tasks within the hybrid OR can facilitate image-guided single-port video-assisted thoracic surgery (iSPVATS), increasing the precision and improving outcomes of the procedure. With the help of a hybrid theatre, catheter-based thermal ablation can provide a safer and less invasive treatment option for select patient groups with early-stage non-small cell lung carcinomas (NSCLC) or metastases. In the future, the combination of hybrid operating room and other inspiring innovative techniques, such as robotic bronchoscopy, 3D-printing, natural orifice transluminal endoscopic surgery (NOTES) lung surgery could lead to a paradigm shift in the way thoracic surgery is conducted.

Autoimmune hepatitis is an idiopathic inflammation of the liver attributed to immune responses against self-antigens presumed to be of hepatocyte origin. It is typically a relapsing and remitting corticosteroid-responsive condition associated with hepatitic serum liver tests, elevated gammaglobulins, and positive immune serology. Histological features are not specific but often include expanded portal tracts with a lymphoplasmacytic infiltrate. Epidemiology: predominantly affects women, may occur throughout life, has some heritable component, and 60% of patients have other autoimmune diseases. Clinical features: many patients are asymptomatic and identified through investigation of abnormal serum liver tests. Presentation may be with anorexia, nausea, hepatic discomfort, and jaundice, but others may have nonspecific malaise or extrahepatic manifestations such as arthralgia, arthritis, or fever. Clinical signs vary greatly, ranging from none to jaundice and tender hepatomegaly to fulminant hepatic failure. One-third of patients present as cirrhotic. Diagnosis: characteristic laboratory findings include elevated serum transaminase activities, hypergammaglobulinaemia (as IgG), and circulating autoantibodies (e.g. antismooth muscle antibodies, anti-liver–kidney microsomal antibodies, and antinuclear antibodies). Diagnosis depends on the combination of clinical features and biochemical, immunological, and liver biopsy abnormalities, with exclusion of viral and other aetiologies. There may be overlap features with other autoimmune liver diseases (primary sclerosing cholangitis or primary biliary cholangitis). Treatment and prognosis: the condition tends to progress to hepatic fibrosis and cirrhosis. Most cases should be treated with an immunosuppressive regimen, typically prednisolone with azathioprine in the first instance, and most require long-term immunosuppression. Crude 10-year survival rate is 65% for those presenting with cirrhosis and greater than 95% for those presenting without. End-stage decompensated cirrhosis and acute nonresponsive autoimmune hepatitis with liver failure can be indications for liver transplantation.

Glomerulonephritis is an important cause of end-stage renal disease worldwide, and treatment strategies have evolved over the past several decades. Immunosuppressive therapies compromise the majority of available therapeutic options. Glucocorticoids, first studied in glomerular disease patients in 1957, remains a first-line therapy for most glomerular diseases. The decision of which cocktail of immunosuppressive therapies to prescribe is not only driven by data but also by patient characteristics and adverse effect profiles. Though the majority of current therapeutic options are globally immunosuppressive therapies, more targeted and less toxic therapies are being developed and tested in clinical trials. An understanding of the mechanisms and efficacy of each of these immunological agents in various glomerular diseases is critical for the nephrologist.

Heart transplantation remains the treatment of choice for end-stage heart failure refractory to conventional treatment. Long-term outcome is excellent, and median survival currently exceeds 13 years. The main causes of death late after transplantation are cardiac allograft vasculopathy and cancer. Medical therapy after transplantation is complex, including immunosuppressive therapy to reduce the risk of graft rejection and prophylaxis against viral and protozoal infections, as well as adjunctive therapy to treat common comorbidities, for instance hypertension. Pharmacological therapy of comorbid conditions requires specific consideration to clinically important interactions with immunosuppressive drugs.

Heart transplantation remains the treatment of choice for end-stage heart failure refractory to conventional treatment. Long-term outcome is excellent, and median survival currently exceeds 13 years. The main causes of death late after transplantation are cardiac allograft vasculopathy and cancer. Medical therapy after transplantation is complex, including immunosuppressive therapy to reduce the risk of graft rejection and prophylaxis against viral and protozoal infections, as well as adjunctive therapy to treat common comorbidities, for instance hypertension. Pharmacological therapy of comorbid conditions requires specific consideration to clinically important interactions with immunosuppressive drugs.

Heart transplantation is a surgical procedure performed on patients with end-stage heart failure or other irreversible heart disease, Heart transplant prolongs the life of severe heart disease patients. Most of the receipts could survive more than 2-3 years, five-year survival rate could reach 70-80% with immunosuppressive therapy, rejection still an important problem after transplantation. Currently, traditional calcineurin inhibitors, antimetabolite agents, and steroids, wildly used after transplantation, the new generation of immunosuppressive medicines have been developed, and cell-based immunotherapy, as mesenchymal stem cell, myeloid-derived suppressor cells, dendritic cells, pluripotent cells and Treg cells are promising to be used in cellular immunotherapy in organ transplantation.

Patients with advanced immunosuppression from AIDS can have a wide variety of causes of diminished alertness (delirium). Diagnostic considerations include results from neuroimaging to rule-out space occupying lesions and permit CSF examination. Presence or absence of other imaging findings especially on MRI of white matter changes, enhancement, or ventriculitis. Serologic testing can be helpful especially in excluding neurosyphilis and cryptococcal disease. Presence of findings outside the CNS (e.g. the lungs, bone marrow, or eyes) can also provide important clues.

Le vitiligo est une leucodermie affectant 0,5 à 1% de la population mondiale. Il n’y a pas de différence de prévalence concernant l’âge, le sexe ou le type de peau. La disparition des mélanocytes entraine une hypopigmentation localisée en plaques symétriques blanches ivoire, à bords nets souvent hyperpigmentés. Les lésions sont le plus souvent retrouvées au niveau des zones découvertes, de frottement et des extrémités. L’évolution des lésions est imprévisible, alternant des phases de développement et de quiescence. Le mécanisme physiopathologique est mal connu, il s’agirait d’une pathologie auto immune avec une prédisposition héréditaire sur un terrain psychologique affaibli. On le retrouve associé dans d’autres affections auto immunes : l’insuffisance surrénalienne, les pathologies thyroïdiennes et la maladie de Biermer (Nagarajan et al (2015)). Le cas clinique rapporté est celui d’une jeune femme de 17 ans, qui présentait une dépigmentation de la lèvre supérieure apparue en octobre 2016. Initialement, la lésion affectait l’hémi lèvre supérieure gauche. Le dermatologue avait posé le diagnostic de vitiligo et instauré un traitement par vitamine C et acide folique, suivi pendant un mois, sans résultat. En juillet 2017 la patiente a consulté en pathologie de la muqueuse buccale car la lésion s’était étendue à l’ensemble de la lèvre supérieure avec atteintes de la commissure labiale gauche et cutanée en regard. L’interrogatoire a révélé un mordillement chronique des lèvres. L’examen de la muqueuse buccale a mis en évidence une dépigmentation linéaire de du bord vermillon de la lèvre supérieure avec renforcement pigmentaire périphérique. L’examen cutané a révélé une plage dépigmentée centimétrique de l’auriculaire de la main droite. Un bilan biologique incluant thyréostimuline, anticorps anti thyroglobuline et anticorps antithyroperoxydase a été prescrit de façon systématique. Il n’a pas révélé d’anomalie. Le traitement prescrit était : tacrolimus à 0,1% en application locale biquotidienne et arrêt de la pathomimie. Le vitiligo des muqueuses buccales est rare. Il a essentiellement été décrit en Inde où la maladie est endémique (Nagarajan et al (2015)). L’atteinte des muqueuses orales concernerait 55% des patients et la lèvre serait touchée dans près d’un cas sur 2 dans cette population. Le cas présenté concernait une patiente originaire d’Afrique du nord. Les études concernant le traitement du vitiligo labial ont été menées uniquement sur le traitement chirurgical : micropigmentation et greffes de mélanocytes semblent avoir le plus fort taux de succès (Gupta et al (2006)). Rodrigues et al (2017) ont conseillé une application locale biquotidienne de tacrolimus 0,1% pour les affections de la face et des zones intertrigineuses. De par son mode d’action, le tacrolimus a une activité immunosuppressive et pourrait favoriser la pigmentation de la muqueuse orale (Fricain et al 2005). Dans le cas présenté, un traitement par tacrolimus a été instauré dans un premier temps. Un traitement chirurgical par greffe de mélanocytes ou un traitement cosmétique sera proposé en cas d’échec du traitement local. Bien que rare, le vitiligo de la muqueuse buccale ne doit pas être ignoré du chirurgien oral qui devra collaborer avec le dermatologue pour définir le traitement adapté.