Transplantation is the treatment of choice for patients with end-stage organ failure. Its success is limited by side effects of immunosuppressive drugs, such as inhibitors of the calcineurin pathway that prevent rejection by reducing synthesis of interleukin-2 by T cells. Moreover, none of the existing drugs efficiently prevent the late development of chronic rejection. Blocking the CD28-mediated T cell costimulation pathway is a non toxic alternative immunosuppression strategy that is currently achieved by blockade of CD80/86, the counter receptors for CD28 on antigenpresenting cells.. However interaction of CD80/86 with CTLA-4 is required for immune regulation. Therefore CD28 blockade, instead of CD80/86 blockade, might preserve regulatory signals mediated by CTLA-4 and favor immune regulation. By using monovalent antibodies, we identified true CD28 antagonists inducing a CTLA-4-dependent decreased T cell function compatible with regulatory T cell (Treg) suppression. In transplantation experiments in primates, blocking CD28 augmented intragraft and peripheral blood regulatory T cells, induced molecular signatures of immune regulation and prevented graft rejection and vasculopathy in synergy with calcineurin inhibition. These findings suggest that targeting costimulation blockade at CD28 favors CTLA-4-dependent immune regulation and promotes allograft survival.

De novo tumors in renal allografts are rare and their prevalence is underestimated. We therefore analyzed renal cell carcinomas arising in renal allografts through a retrospective French renal transplant cohort. We performed a retrospective, multicentric survey by sending questionnaires to all French kidney transplantation centers. All graft tumors diagnosed after transplantation were considered as de novo tumors. Thirty-two centers participated in this study. Seventy-nine tumors were identified among 41 806 recipients (Incidence 0.19%). Patients were 54 men and 25 women with a mean age of 47 years old at the time of diagnosis. Mean tumor size was 27.8 mm. Seventy-four (93.6%), 53 (67%) and 44 tumors (55.6%) were organ confined (T1-2), low grade (G1-2) and papillary carcinomas, respectively. Four patients died of renal cell carcinomas (5%). The mean time lapse between transplantation and RCC diagnosis was 131.7 months. Thirty-five patients underwent conservative surgery by partial nephrectomy (n = 35, 44.3%) or radiofrequency (n = 5; 6.3%). The estimated 5 years cancer specific survival rate was 94%. Most of these tumors were small and incidental. Most tumors were papillary carcinoma, low stage and low grade carcinomas. Conservative treatment has been preferred each time it was feasible in order to avoid a return to dialysis.

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These authors contributed equally to the senior authorship of this study.Selective targeting of CD28 might represent an effective immunomodulation strategy by preventing T cell costimulation, while favoring coinhibition since inhibitory signals transmitted through CTLA-4; PD-L1 and B7 would not be affected. We previously showed in vitro and in vivo that anti-CD28 antagonists suppress effector T cells while enhancing regulatory T cell (Treg) suppression and immune tolerance. Here, we evaluate FR104, a novel antagonist pegylated anti-CD28 Fab' antibody fragment, in nonhuman primate renal allotransplantation. FR104, in association with low doses of tacrolimus or with rapamycin in a steroid-free therapy, prevents acute rejection and alloantibody development and prolongs allograft survival. However, when FR104 was associated with mycophenolate mofetil and steroids, half of the recipients rejected their grafts prematurely. Finally, we observed an accumulation of Helios-negative Tregs in the blood and within the graft after FR104 therapy, confirmed by Tregspecific demethylated region DNA analysis. In conclusion, FR104 reinforces immunosuppression in calcineurin inhibitor (CNI)-low or CNI-free protocols, without the need of steroids. Accumulation of intragraft Tregs suggested the promotion of immunoregulatory mechanisms. Selective CD28 antagonists might become an alternative CNI-sparing strategy to B7 antagonists for kidney transplant recipients.

Acute antibody-mediated rejection is an unsolved issue in transplantation, especially in the context of pretransplant immunization. The deleterious effect of preformed cytotoxic anti-HLA antibodies through complement activation is well proven, but very little is known concerning complement blockade to prevent/cure this rejection. Here, we used a baboon model of preimmunization to explore the prevention of acute antibody-mediated rejection by an early inhibition of the classical complement pathway using human recombinant C1-inhibitor. Baboons were immunized against peripheral blood mononuclear cells from allogeneic donors and, once a specific and stable immunization had been established, they received a kidney from the same donor. Rejection occurred at day 2 posttransplant in untreated presensitized recipients, with characteristic histological lesions and complement deposition. As recombinant human C1-inhibitor blocks in vitro cytotoxicity induced by donor-specific antibodies, other alloimmunized baboons received the drug thrice daily intravenously during the first 5 days after transplant. Rejection was prevented during this treatment but occurred after discontinuation of treatment. We show here that early blockade of complement activation by recombinant human C1-inhibitor can prevent acute antibody-mediated rejection in presensitized recipients. This treatment could also be useful in other forms of acute antibody-mediated rejection caused by induced antibodies.

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What ' s known on the subject? and What does the study add? Patients with end-stage renal disease (ESRD) have an increased risk of developing RCC in their native kidneys. The prevalence of RCC is 3 -4% in cases of ESRD in dialyzed and/or transplanted patients, which corresponds to a rate 100-times higher than that in the general population. This is the fi rst study, to our knowledge, comparing the characteristics of kidney cancer in the ESRD population according to their dialysis or transplantation status at the time of diagnosis. The differences in stage and survival we observed may be due to differences in surveillance strategies between transplanted and not transplanted patients, nevertheless, the differences in pathological subtypes suggest they could also be due to differences in the tumorigenesis process. OBJECTIVE• To compare clinical, pathological and outcome features of renal cell carcinomas (RCCs) arising in patients with chronic renal failure (CRF) with or without renal transplantation. PATIENTS AND METHODS• In all, 24 French University Departments of Urology and Kidney Transplantation participated in this retrospective study comparing RCCs arising in patients with CRF according to their dialysis or transplantation status at the time of diagnosis.• Information about age, sex, symptoms, duration of CRF, mode and duration of dialysis, renal transplantation, tumour staging and grading, histological subtype and outcome were recorded in a unique database.• Qualitative and quantitative variables were compared by using chi-square and Student statistical analysis. Survival was assessed by Kaplan -Meier and Cox methods. RESULTS• Data on 303 RCC cases diagnosed between 1985 and 2009 were identifi ed in 206 men (76.3%) and 64 women (23.7%).• Transplanted and not transplanted patients accounted for 213 (70.3%) and 90 cases (29.7%), respectively.• In transplant recipients, RCC was diagnosed at a younger age [ mean ( SD ) 53 (11) vs 61 (14) years, P < 0.001), the mean tumour size was smaller [ 3.4 (2.3) vs 4.2 (3.1) cm, P = 0.02), pT1a stage (75 vs 60%, P = 0.009) and papillary histological subtype (44 vs 22%, P < 0.001) were more frequent than in their dialysis-only counterparts.• Nodal (1 vs 6%, P = 0.03) and distant metastases rates (0 vs 5%, P < 0.001) were signifi cantly increased in patients who had not had a transplant. However, F ü rhman grading, symptoms, tumour multifocality or bilaterality, presence of acquired cystic kidney disease, were not signifi cantly different between the groups. Study Type -Prognosis (case series) Level of Evidence 4

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