Blockade of C3aR/C5aR signaling in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival.

The significance of human leukocyte antigen (HLA) compatibility and preformed antibodies in liver transplantation remains unclear. The objectives of this study were to evaluate, in a single-center cohort comprising 896 liver transplants, whether the degree of donor-recipient compatibility and preformed antibodies modified graft survival. Univariate Kaplan-Meier analysis demonstrated that donor-recipient HLA compatibility had a marginal impact on allograft survival. As for compatibility at individual antigen loci, 2 mismatches at HLA-A conferred a survival advantage in retransplanted allografts (P ϭ 0.011). HLA-B and HLA-DR loci did not play a significant role in outcome in any pathology. The concordance of results on preformed antibodies detected by complement-dependent cytotoxicity (CDC) and a multiple bead assay (Luminexா xMAP) showed a strong correlation between both techniques (P Ͻ 0.0001). Both CDC-detected and Luminex-detected antibodies were associated with shorter graft survival within the first year post-transplant (P ϭ 0.01 and P ϭ 0.016, respectively). Positive CDC T crossmatches and Luminex-detected HLA class II antibodies played a significant role in decreasing graft survival (P ϭ 0.043 and P ϭ 0.0019 at 1 year, respectively, and P ϭ 0.005 and P ϭ 0.038 at 5 years, respectively). A correlation was also observed between the presence of preformed Luminex-detected class II or Luminex I and II antibodies and allograft rejection (P ϭ 0.001 and P ϭ 0.042, respectively). In conclusion, although HLA typing is not a prerequisite for transplantation, screening of HLA antibodies with Luminex techniques and CDC crossmatch may be useful in the detection of at-risk patients that could benefit from increased surveillance and tailored therapy following transplantation. Liver Transpl 14: 554-562, 2008. © 2008 AASLD. Received June 26, 2007 accepted October 29, 2007. In many end-stage liver diseases, hepatic transplantation often constitutes the only therapeutic option available.1-3 Studies performed in clinical solid organ transplants have endeavored to gain insight into immunological parameters that could be important in altering the course of allograft tolerance, thus modifying the prognosis.Two main factors, donor-recipient human leukocyte antigen (HLA) compatibility and the absence of preformed, donor-specific anti-HLA cytotoxic antibodies (giving rise to a positive crossmatch), are known to contribute to a more favorable outcome in renal 4-6 and heart transplants. 7 This has not been the case in liver transplantation. Over the past 2 decades, opinions

CD4+Foxp3+ regulatory T cells (Treg) are critical regulators of immune homeostasis and self-tolerance. Whereas thymic-derived or natural Treg (nTreg) stably express Foxp3, adaptive or induced Treg (iTreg) generated from peripheral CD4 T cells are susceptible to inflammation-induced reversion to pathogenic effector T cells (Teff). Building upon our previous observations that T cell-expressed receptors for C3a (C3aR) and C5a (C5aR) drive Th1 maturation, we tested the impact of C3aR/C5aR signaling on induction and stability of alloreactive iTreg. We observed that genetic deficiency or pharmacological blockade of C3aR/C5aR signaling augments murine and human iTreg generation, stabilizes Foxp3 expression, resists iTreg conversion to IFNγ/TNFα-producing Teff, and as a consequence, limits the clinical expression of graft-versus-host disease. Together the findings highlight the expansive role of complement as a crucial modulator of T cell alloimmunity and demonstrate proof-of-concept that targeting C3a/C3aR and C5a/C5aR interactions could facilitate iTreg-mediated tolerance to alloantigens in humans.

SummarySerial monitoring of peripheral blood lymphocyte subpopulations (PBLSs) counts might be useful in predicting post-transplant opportunistic infection (OI) after kidney transplantation (KT). PBLSs were prospectively measured in 304 KT recipients at baseline and post-transplant months 1 and 6. Areas under receiver operating characteristic curves were used to evaluate the accuracy of different subpopulations in predicting the occurrence of overall OI and, specifically, cytomegalovirus (CMV) disease. We separately analyzed patients not receiving (n = 164) or receiving (n = 140) antithymocyte globulin (ATG) as induction therapy. In the non-ATG group, a CD8 + T-cell count at month 1 <0.100 9 10 3 cells/ll had negative predictive values of 0.84 and 0.86 for the subsequent occurrence of overall OI and CMV disease, respectively. In the multivariate Cox model, a CD8 + T-cell count <0.100 9 10 3 cells/ll was an independent risk factor for OI (adjusted hazard ratio: 3.55; P-value = 0.002). In the ATG group, a CD4 + T-cell count at month 1 <0.050 9 10 3 cells/ll showed negative predictive values of 0.92 for the subsequent occurrence of overall OI and CMV disease. PBLSs monitoring effectively identify KT recipients at low risk of OI, providing an opportunity for individualizing post-transplant prophylaxis practices.

No abstract

SummaryThe purpose of this study is to evaluate the effects of neonatal thymectomy in the functional capacity of the immune system. We selected a group of 23 subjects, who had undergone thymectomy in their first 30 days of life, during an intervention for congenital heart disease. Several parameters of the immune system were evaluated during their first 3 years of life. Lymphocyte populations and subpopulations (including naive, memory and effector subpopulations), T cell receptor (TCR) Vb repertoire, response of T cells following in vitro stimulation by mitogen, quantification of immunoglobulins, TCR excision circles (TRECS) and interleukin (IL)-7 were measured. We found that neonatal thymectomy produces long-term diminution in total lymphocyte counts, especially in naive CD4+ and CD8 + T cells. Additionally, TRECS were decreased, and plasma IL-7 levels increased. A statistically significant negative correlation was found between absolute CD4 + T cells and IL-7 (r = -0·470, P = 0·02). The patients did not suffer more infectious events than healthy control children, but thymectomy in neonates resulted in a significant decrease in T lymphocyte levels and TRECS, consistent with cessation of thymopoiesis. This could produce a compromise in immune function later in life, especially if the patients suffer T cell depletion and need a reconstitution of immune function.

We aimed to analyze the incidence, risk factors and impact of hypogammaglobulinemia (HGG) in 226 kidney transplant (KT) recipients in which serum immunoglobulin (Ig) levels were prospectively assessed at baseline, month 1 (T 1 ), and month 6 (T 6 ). The prevalence of IgG HGG increased from 6.6% (baseline) to 52.0% (T 1 ) and subsequently decreased to 31.4% (

Acute graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic cell transplantation (allo-HCT) that results from donor allogeneic T cell attack on host tissues. Based on previous work implicating immune cell-derived C3a and C5a as regulators of T cell immunity, we examined the effects of locally produced C3a and C5a on murine T cell-mediated GvHD. We found that total body irradiation, a conditioning regimen required to permit engraftment of allo-HCT, caused upregulation and activation of alternative pathway complement components by recipient APCs. Allo-HCT with decay accelerating factor-null (Daf1 -/-) host BM and Daf1 -/-donor lymphocytes led to exacerbated GvHD outcome and resulted in splenic and organinfiltrating T cell expansion. T cells deficient in C3a receptor (C3aR) and/or C5a receptor (C5aR) responded weakly in allogeneic hosts and exhibited limited ability to induce GvHD. Using a clinically relevant treatment strategy, we showed that pharmacological C5aR blockade reduced GvHD morbidity. Our data mechanistically link APC-derived complement to T cell-mediated GvHD and support complement inhibition as a therapeutic strategy for GvHD in humans.