Viral infections, including cytomegalovirus (CMV), abrogate transplantation tolerance in animal models. Whether this also occurs in humans remains elusive. We investigated how CMV affects T cells and rejection episodes after liver transplantation (LT). Phenotype and alloreactivity of peripheral and allograftinfiltrating T cells from LT patients with different CMV status were analyzed by flow cytometry. The association of CMV status with early and late acute rejection was retrospectively analyzed in a cohort of 639 LT patients. CMV-positivity was associated with expansion of peripheral effector memory T cell subsets after LT. Patients with CMV primary infection showed donor-specific CD8 þ T cell hyporesponsiveness. While terminally differentiated effector memory cells comprised the majority of peripheral donor-specific CD8 þ T cells in CMV primary infection patients, they were rarely present in liver allografts. Retrospective analysis showed that R À D þ serostatus was an independent protective factor for late acute rejection by multivariate Cox regression analysis (hazard ratio [HR] ¼ 0.18, 95% CI ¼ 0.04-0.86, p ¼ 0.015). Additionally, CMV primary infection patients showed the highest Vd1/Vd2 gd T cell ratio, which has been shown to be associated with operational tolerance after LT. In conclusion, our data suggest that CMV primary infection may promote tolerance to liver allografts, and CMV status should be considered when tapering or withdrawing immunosuppression.
Background: The cytotoxic T lymphocyte antigen 4 (CTLA-4) gene encodes for a membrane bound (mCTLA-4) and a soluble (sCTLA-4) isoform, which are both involved in regulation of T cell function. The CTLA-4 +49A/G single nucleotide polymorphism (SNP) influences expression of mCTLA-4; +6230G/A SNP affects the production of sCTLA-4. Aim: To examine whether these functional SNPs influence the rate of rejection after liver transplantation. Patients and methods: Liver graft recipients (n = 483) were genotyped for both SNPs, and haplotypes were reconstructed. Association with rejection was tested by the log rank test using the Kaplan-Meier method with time to the first acute rejection episode as outcome. Multiple analysis of SNPs together with demographic factors was performed by Cox regression. Results: Three haplotypes were observed in the cohort: +49A/+6230A, +49A/+6230G, and +49G/+6230G. The +49A/+6230G haplotype was significantly and dose dependently associated with acute rejection (p = 0.01). Of the demographic factors tested, only underlying liver disease was significantly associated with rejection. Adjusted for underlying liver disease, each additional +49A/ +6230G haplotype allele resulted in a significantly higher risk of acute rejection (risk ratio 1.34 (95% confidence interval 1.04-1.72); p = 0.02). Patients who lacked this haplotype had the lowest, carriers an intermediate, and homozygotes the highest risk of acute rejection. Conclusion: The CTLA-4 +49A/+6230G haplotype, which encodes for normal mCTLA-4 expression but reduced sCTLA-4 production, is a co-dominant risk allele for acute rejection after clinical liver transplantation. This implies that even under immunosuppression, CTLA-4 is critically involved in the regulation of the human immune response to allogeneic grafts.
Conventional assays for quantification of allo-reactive T-cell precursor frequencies (PF) are relatively insensitive. We present a robust assay for quantification of PF of T-cells with direct donor-specificity, and establish the kinetics of circulating donor-specific T cells after liver transplantation (LTx). B cells from donor splenocytes were differentiated into professional antigen-presenting cells by CD40-engagement (CD40-B cells). CFSE-labelled PBMC from LTx-recipients obtained before and at several time points after LTx, were stimulated with donor-derived or 3rd party CD40-B cells. PF of donor-specific T cells were calculated from CFSE-dilution patterns, and intracellular IFN-γ was determined after re-stimulation with CD40-B cells. Compared to splenocytes, stimulations with CD40-B cells resulted in 3 to 5-fold higher responding T-cell PF. Memory and naïve T-cell subsets responded equally to allogeneic CD40-B cell stimulation. Donor-specific CD4+ and CD8+ T-cell PF ranged from 0.5 to 19% (median: 5.2%). One week after LTx, PF of circulating donor-specific CD4+ and CD8+ T cells increased significantly, while only a minor increase in numbers of T cells reacting to 3rd party allo-antigens was observed. One year after LTx numbers of CD4+ and CD8+ T cells reacting to donor antigens, as well as those reacting to 3rd party allo-antigens, were slightly lower compared to pre-transplant values. Moreover, CD4+ and CD8+ T cells responding to donor-derived, as well as those reacting to 3rd party CD40-B cells, produced less IFN-γ. In conclusion, our alternative approach enables detection of allo-reactive human T cells at high frequencies, and after application we conclude that donor-specific T-cell PF increase immediately after LTx. However, no evidence for a specific loss of circulating T-cells recognizing donor allo-antigens via the direct pathway up to 1 year after LTx was obtained, underscoring the relative insensitiveness of previous assays.
An individual's risk of developing CKD after LT is not associated with genetic variation in either recipient or donor CYP3A5 or ABCB1 genotype status.
Introduction: solid organ transplantation has been applied for decades, but outcomes for somatic cell transplants remain poor. Similarly in animal models, liver transplants are spontaneously accepted in mice, while hepatocyte transplants are acutely rejected, suggesting a crucial role of liver non-parenchymal cells in immune regulation. We have identified that liver stromal cells, hepatic stellate cells (HSC) can actively suppress T cell response. Co-transplantation with HSC effectively protects allogeneic islet grafts from rejection. This is associated with accumulation of CD11b + CD11cmononuleocytes in grafts, instead of CD11c + DC as in islet alone group. These CD11b + CD11ccells share many properties with myeloid-derived suppressor cells (MDSC). HSC have been shown to be potent inducers of MDSC in vitro via soluble factors, including complement component 3 (C3). Quiescent HSC express low C3, while expression is upregulated upon exposure to IFN-g or activated T cells. The aim of this study was to test the role of C3 in induction of MDSC in vivo. Methods and Results: 3 x 10 5 HSC isolated from wild type (WT) or C3 KO mice (both B6 background) were mixed with 300 islets (BALB/c), and transplanted into streptozotocin-induced diabetic B6 recipients, achieving long-term survival (>90d) in 60% of islet grafts, while all islet alone grafts were rejected within 15 days (p<0.05). None of islet grafts co-transplanted with C3 -/-HSC survived only 15.4 2.5 days. To investigate mechanisms, islet grafts, draining and irrelevant LN and spleen were collected on POD 7 for histochemical study. Co-transplantation with WT HSC was associated with increase in apoptosis in CD8 + T cells, enhancement of CD4 + FoxP3 + Treg cells, and accumulation of CD11b + CD11ccells in the grafts. Flow analysis of graft infiltrating CD11b + cells showed characteristics of MDSC, including expression of high GR-1, arginase 1 and iNOS, but low costimulatory molecules, capacity of inhibiting T cell proliferation and CTL activity, but enhancing T cell apoptosis. Interestingly, CD11b + cells from the grafts co-transplanted with C3 -/-HSC largely lost the MDSC properties of MDSC, expressing low arginase and iNOS, and failing to inhibit T cell response and induce T cell apoptosis. Conclusion: C3 produced by co-transplanted HSC plays a crucial role in generation of MDSC, which leads to protection of islet transplants from host immune attack.
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