Regulatory T cells in alloreactivity after clinical heart transplantation.

Purpose Of Review: As the knowledge of CD4+CD25bright+FoxP3+ regulatory T cells in experimental transplant models grows, we need to understand how and to what extent these suppressor cells regulate donor-directed immune events in the transplantation clinic. This review focuses on the function of regulatory T cells in the peripheral blood and the transplanted organ of patients after heart transplantation during immunological quiescence and rejection.

Recent Findings: Here, we present data that peripheral CD4+CD25bright+FoxP3+ T cells of heart transplant patients who experience acute rejection have inadequate immune regulatory function in vitro compared with those of nonrejecting patients.

Interpatient variability in IMPDH activity in MMF-treated renal transplant patients is correlated with IMPDH type II 3757T > C polymorphism.

Objectives: The active metabolite of mycophenolate mofetil (MMF), mycophenolic acid, inhibits the activity of the target enzyme inosine monophosphate dehydrogenase (IMPDH). The aim of this study was to correlate eight different single nucleotide polymorphisms of the IMPDH type II gene to the activity of the IMPDH enzyme to explain between-patient differences in IMPDH activity.

Methods And Results: In a prospective study, we measured IMPDH activity, mycophenolic acid plasma concentrations, and eight polymorphisms of IMPDH type II in de novo kidney transplant recipients, 6 days posttransplantation while on MMF treatment.

Non-HLA T-cell reactivity during the first year after HLA-identical living-related kidney transplantation.

Background: It has been reported that donor-reactive T-cell responses may decrease during the first year after HLA-mismatched organ transplantation. We wondered whether donor-reactive T-cell responses directed to minor histocompatibility antigens (mHAgs) or other non-HLA antigens also decrease after HLA-identical living-related (LR) kidney transplantation.

Methods: We studied donor-reactive T-cell responses by IFN-gamma and granzyme B (GrB) Elispot assays in 15 HLA-identical LR kidney transplant recipients before, six months and one yr after transplantation.

A multiplex bead array analysis to monitor donor-specific cytokine responses after withdrawal of immunosuppression in HLA-identical living related kidney transplant patients.

Immune reactivity after HLA-identical living related (LR) kidney transplantation can be caused by minor histocompatibility antigen and non-HLA antigen mismatches between donor and recipient. In our center, HLA-identical LR kidney transplant recipients receive azathioprine (AZA) or mycophenolate mofetil (MMF) in combination with corticosteroids for 1 year after transplantation. Thereafter, AZA or MMF was withdrawn, and the patients were treated with steroid monotherapy as maintenance therapy.

Pre-kidney-transplant blood transfusions do not improve transplantation outcome: a Dutch national study.

Background: Female renal transplant candidates are prone to be sensitized by prior pregnancies, and undetected historical sensitization might decrease transplantation outcome. Hypothesis of our study was that pre-transplant blood transfusions (PTFs) can elucidate historical sensitization and that the avoidance of the associated antigens can improve transplantation outcome.

Methods: Data from all female non-immunized renal transplant candidates who received a random PTF (rPTF) (n = 620), matched PTF (mPTF) (one HLA-A and B and one HLA-DR match) (n = 86) or donor-specific blood transfusion (DST) (n = 100) between 1996 and 2006 were collected.

Deficient TNF-alpha and IFN-gamma production correlates with nondetectable donor-specific cytotoxicity after clinical kidney transplantation.

Background: We previously reported that no cytotoxic T-lymphocyte precursor frequencies (CTLpf) were found in 60% of patients on azathioprine or mycophenolate mofetil+Pred long after kidney transplantation. We questioned whether the absence of donor-specific CTLpf was associated with low levels of stimulatory Th1 (tumor necrosis factor [TNF]-alpha, interferon [IFN]-gamma) or high levels of regulatory Th2 (interleukin [IL]-4, IL-6, IL-10) cytokines.

Methods: In this study, peripheral blood monocyte cells (PBMC) were stimulated with irradiated donor cells.

Monotherapy rapamycin allows an increase of CD4 CD25 FoxP3 T cells in renal recipients.

CD4(+) CD25(bright+) FoxP3(+) regulatory T cells (Tregs) may control donor-specific allogeneic responses in kidney transplant recipients. Recent evidence demonstrated that three phenotypical Treg-subsets, naive (CCR7(+)CD45RO(-)), central-memory (CCR7(+)CD45RO(+)) and effector-memory (CCR7(-)CD45RO(+)), are essential for the development and function of antigen-specific suppression in the lymphoid and peripheral tissues. Also, it has been appreciated that Tregs are affected by immunosuppressive agents.

Clinical rejection and persistent immune regulation in kidney transplant patients.

We evaluated whether the regulatory function of CD4(+)CD25(high+)FoxP3(+) T-cells from patients on tacrolimus and mycophenolate mofetil (MMF) is affected by preceding steroid and anti-CD25 mAb induction therapy and whether this function is associated with rejection after kidney transplantation. Kidney recipients (N=15) were randomized to receive either anti-CD25 mAb induction (i.e.

Inadequate immune regulatory function of CD4+CD25bright+FoxP3+ T cells in heart transplant patients who experience acute cellular rejection.

Background: CD4CD25FoxP3 regulatory T cells are suppressors of antigen-activated immune reactivity. Here, we assessed the clinically relevant role of these cells in the control of immune responses directed to a transplanted heart.

Methods: We investigated the phenotype and function of peripheral CD4CD25FoxP3 T cells in heart transplant patients free from acute rejections (n=9) and in rejectors (n=12) before and during acute cellular rejection.

Strategies to advance living kidney donation: a single center's experience.

In Europe, living kidney donation rates differ considerably from country to country. These differences are related to deceased kidney donation rates: countries with higher deceased donation rates have lower living donation rates. Despite the differences, all countries have one thing in common, namely, the shortage of kidneys for transplantation.

T-cell reactivity during tapering of immunosuppression to low-dose monotherapy prednisolone in HLA-identical living-related renal transplant recipients.

Background: In many transplant centers, human leukocyte antigen (HLA)-identical living-related (LR) renal transplant recipients receive standard maintenance immunosuppression from 1 year after transplantation. We questioned whether discontinuation of azathioprine (AZA) or mycophenolate mofetil (MMF) influenced T-cell reactivity, circulating dendritic cell (DC) subsets numbers and their maturation status.

Methods: Twenty-nine HLA-identical LR renal transplant recipients were withdrawn from AZA or MMF.

Donor-derived mesenchymal stem cells suppress alloreactivity of kidney transplant patients.

Background: Human mesenchymal stem cells (MSC) have immunosuppressive capacities. Although their efficacy is currently studied in graft-versus-host disease, their effect on alloreactivity in solid organ transplant patients is unknown. In this study, the immunosuppressive effect of MSC on recipient anti-donor reactivity was examined before and after clinical kidney transplantation.

Laparoscopic donor nephrectomy: a plea for the right-sided approach.

Background: Laparoscopic donor nephrectomy (LDN) has become the preferred procedure for live donor nephrectomy. Most transplant surgeons are reluctant toward right-sided LDN (R-LDN) fearing short vessels and renal vein thrombosis.

Methods: In our institution, selection of the appropriate kidney for donation was based on the same criteria that traditionally governed open donor nephrectomy.

Successful tapering of immunosuppression to low-dose monotherapy steroids after living-related human leukocyte antigen-identical renal transplantation.

Background: Living-related (LR) human leukocyte antigen (HLA)-identical renal transplant (RTx) recipients often receive standard immunosuppression, despite the absence of mismatched major HLA-antigens and the known complications of long-term use of immunosuppression. No data are available on the need for immunosuppression for these specific patients. We wondered whether their immunosuppressive load could be radically reduced.

Long-term survival after kidney transplantation in an HIV-positive patient.

Only a decade ago, human immunodeficiency virus (HIV)-seropositivity was considered an absolute contraindication for organ transplantation. With the currently available experience, it is no longer justified to deny HIV-positive patients access to transplantation. To the best of our knowledge, we here present the longest surviving HIV-positive patient after renal transplantation.

Generation of donor-specific regulatory T-cell function in kidney transplant patients.

Background: In the search for mechanisms that can induce and maintain transplant tolerance, donor-specific CD4CD25FoxP3 regulatory T cells have been frequently mentioned. However, it remains to be demonstrated, whether these cells are generated after clinical transplantation.

Methods: We prospectively analyzed the phenotype and function of peripheral regulatory CD4CD25 T cells of 79 patients before, 3, 6, and 12 months after kidney transplantation.

Early living-donor kidney transplantation: a review of the associated survival benefit.

Avoidance of dialysis-related morbidity, improvement in quality of life, and reduction of costs have been mentioned as advantages of preemptive kidney transplantation. However, this therapeutic option is underutilized. Previous studies assessing the patient survival benefit of preemptive kidney transplantation compared it with postdialysis kidney transplantation.

End-stage renal failure and regulatory activities of CD4+CD25bright+FoxP3+ T-cells.

Background: The defensive immune system in patients with end-stage renal failure is impaired at multiple levels. This state of immune incompetence is associated with continuous activation of the immune system. An additional explanation for this state of activation may be the disturbed function of CD4(+)CD25(bright+)FoxP3(+) regulatory T-cells.

The effect of rabbit anti-thymocyte globulin induction therapy on regulatory T cells in kidney transplant patients.

Background: Prevention of alloreactivity by rabbit anti-thymocyte globulins (rATG) may not only result from immunodepletion but also from the induction of T cells that control allogeneic immune responses. In the present prospective and controlled study, we investigated the effect of rATG on the frequency, function and phenotype of peripheral immunoregulatory CD4+ T cells in kidney transplant (KTx) patients.

Methods: After transplantation, 16 patients received ATG-induction therapy and triple therapy consisting of tacrolimus, MMF and steroids.

The effect of the JAK inhibitor CP-690,550 on peripheral immune parameters in stable kidney allograft patients.

Introduction: CP-690,550 inhibits Janus kinase 3 (JAK3) which mediates signal transduction of receptors of the common gamma-chain cytokines. These cytokines play key roles in lymphocyte function and homeostasis. As part of a phase 1 trial, we evaluated the effect of CP-690,550 on immune parameters.

Donor-specific immune regulation by CD8 lymphocytes expanded from rejecting human cardiac allografts.

To assess whether regulatory T cells are present in rejecting human cardiac allografts, we performed functional analyses of graft lymphocytes (GLs) expanded from endomyocardial biopsies (EMB; n = 5) with histological signs of acute cellular rejection. The GL cultures were tested for their proliferative capacity and regulatory activity on allogeneic-stimulated peripheral blood mononuclear cells (PBMC) of the patient (ratio PBMC:GLs = 5:1). Three of these GL cultures were hyporesponsive to donor antigens and suppressed the antidonor proliferative T-cell response of PBMC, but not the anti-third-party response.

On chain lengths, domino-paired and unbalanced altruistic kidney donations.

Kidney transplantations with living related and unrelated donors are the optimal option for patients with end-stage renal disease. For patients with a willing--but blood-type or HLA incompatible donor--a living-donor kidney exchange program could be an opportunity. In Asia, the United States and Europe, kidney exchange programs were developed under different conditions, with different exchange algorithms, and with different match results.

Hurdles, barriers, and successes of a national living donor kidney exchange program.

Background: Living donor kidney exchange is now performed in several countries. However, no information is available on the practical problems inherent to these programs. Here, we describe our experiences with 276 couples enrolled in the Dutch program.