Naturally occurring CD4+ TR cells that express CD25 and the transcription factor FoxP3 play a key role in immune homeostasis preventing immune pathological responses to self and foreign antigens. CTLA-4 is expressed by a high percentage of these cells, and is often considered as a marker for TR in experimental and clinical analysis. However, it has not yet been proven that CTLA-4 has a direct role in TR function. Using a colitis transfer model, we previously showed that anti-CTLA-4 mAb treatment abrogates suppression of colitis mediated by CD4+ CD25+ TR. Here we demonstrate that anti-CTLA-4 mAb treatment inhibits TR function via direct effects on CTLA-4 expressing TR cells, and not via hyper-activation of colitogenic T cells. Although anti-CTLA-4 mAb treatment completely inhibits TR function, it does not affect TR cell expansion, persistence or homing to the gut-associated lymphoid tissue, indicative of the blockade of a signal required for TR cell activity. In contrast to the striking effect of the antibody, CTLA-4 deficient mice can produce functional TR cells, suggesting that compensatory mechanisms can develop. This study provides direct evidence that CTLA-4 has a specific, non-redundant role in the function of normal regulatory T cells. This role has to be taken into account when targeting CTLA-4 for therapeutic purposes, as such a strategy will not only boost effector T cell responses, but might also break TR-mediated self-tolerance.

There are no conflicts of interest to report.The use of living donors for kidney transplantation in the United States is common, and long-term studies have demonstrated the safety of donation by young, healthy individuals. However, transplant programs have little data to guide them in deciding which donors are unacceptable, and which characteristics are associated with kidney disease or poor psychosocial outcomes after donation. To document current practices in evaluating potential donors, we surveyed all US kidney transplant programs. Compared to a survey 12 years ago, medical criteria for donation are more inclusive in several areas. All responding programs now accept living unrelated donors. Most programs no longer have an upper age limit to be eligible. Programs are now more likely to accept donors with treated hypertension, or a history of kidney stones, provided that certain additional criteria are met. In contrast, medical criteria for donation are more restrictive in other areas, such as younger donor age and low creatinine clearance. Overall, significant variability remains among transplant programs in the criteria used to evaluate donors. These findings highlight the need for more data on long-term outcomes in various types of donors with potential morbidities related to donation.

Live donor kidney transplantation is the best treatment option for most patients with late-stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. A consensus conference was held June 5–6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation.

Background Blacks receive live donor kidney transplantation (LDKT) less often than patients of all other races. We evaluated the effectiveness of educational interventions in removing barriers to LDKT for blacks. Methods Patients were randomized to three interventions in which health educator(s) delivered an intervention to (a) the patient and his/her guests in the patient’s home (House Calls, HC n=54), (b) clusters of patients and their guests in the transplant center (Group-Based, GB n=49), (c) the individual patient alone in the transplant center (Individual Counseling, IC n=49). Results At the 2-year endpoint, 15% (8), 8% (4), and 6% (3) of HC, GB, and IC patients, respectively, received LDKT (p=0.30). HC patients were more likely than GB and IC patients to have at least one donor inquiry (82% vs. 61% vs. 47%, p=0.001) and evaluation (65% vs. 39% vs. 27%, p<0.001). HC patients also were more likely to have higher knowledge, fewer concerns, and higher willingness to talk to others about donation 6 weeks post- intervention. Conclusions These findings underscore the importance of including the patient’s social network in LDKT education and the potential of the HC intervention to reduce racial disparity in LDKT rates.

We conducted a survey of 132 US kidney transplant programs to examine how they evaluate and select potential living kidney donors, focusing on donorrecipient relationships, psychosocial criteria, and consent processes. There is heterogeneity in donorrecipient relationships that are considered acceptable, although most programs (70%) will not consider publicly solicited donors. Most programs (75%) require a psychosocial evaluation for all potential living donors. Most programs agree that knowledge of financial reward (90%), active substance abuse (86%), and active mental health problems (76%) are absolute contraindications to donation. However, there is greater variability in how other psychosocial issues are considered in the selection process. Consent processes are highly variable across programs: donor and recipient consent for the donor evaluation is presumed in 57% and 76% of programs, respectively. The use of 13 different informed consent elements varied from 65% (alternative donation procedures) to 86% (description of evaluation, surgery and recuperative period) of programs. Forty-three percent use a 'cooling off' period. Findings demonstrate high variability in current practice regarding acceptable donor-recipient relationships, psychosocial criteria, and consent processes. Whether greater consensus should be reached on these donor evaluation practices, especially in the context of more expansive use of living donor kidney transplantation, is discussed.

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T cell costimulation by B7 molecules plays an important role in the regulation of alloimmune responses. Although both B7-1 and B7-2 bind CD28 and CTLA-4 on T cells, the role of B7-1 and B7-2 signaling through CTLA-4 in regulating alloimmune responses is incompletely understood. To address this question, we transplanted CD28-deficient mice with fully allogeneic vascularized cardiac allografts and studied the effect of selective blockade of B7-1 or B7-2. These mice reject their grafts by a mechanism that involves both CD4+ and CD8+ T cells. Blockade of CTLA-4 or B7-1 significantly accelerated graft rejection. In contrast, B7-2 blockade significantly prolonged allograft survival and, unexpectedly, reversed the acceleration of graft rejection caused by CTLA-4 blockade. Furthermore, B7-2 blockade prolonged graft survival in recipients that were both CD28 and CTLA-4 deficient. Our data indicate that B7-1 is the dominant ligand for CTLA-4-mediated down-regulation of alloimmune responses in vivo and suggest that B7-2 has an additional receptor other than CD28 and CTLA-4 to provide a positive costimulatory signal for T cells.

The annual number of living kidney donors in the United States peaked at 6,647 in 2004. The preceding decade saw a 120% increase in living kidney donation. However, since 2004, living kidney donation has declined in all but one year, resulting in a 13% decline in the annual number of living kidney donors from 2004 to 2011. The proportional decline in living kidney donation has been more pronounced among men, blacks, younger adults, siblings, and parents. In this paper, we explore several possible explanations for the decline in living kidney donation, including an increase in medical unsuitability, an aging transplant patient population, financial disincentives, public policies, and shifting practice patterns, among others. We conclude that the decline in living donation is not merely reflective of random variation, but one that warrants action by transplant centers, the broader transplant community, and state and national governments.