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Background: Belatacept, an inhibitor of the CD28-CD80/86 costimulatory pathway, allows for calcineurin-inhibitor free immunosuppressive therapy in kidney transplantation but is associated with a higher acute rejection risk than ciclosporin. Thus far, no biomarker for belatacept-resistant rejection has been validated. In this randomized-controlled trial, acute rejection rate was compared between belatacept- and tacrolimus-treated patients and immunological biomarkers for acute rejection were investigated., Methods: Forty kidney transplant recipients were 1:1 randomized to belatacept or tacrolimus combined with basiliximab, mycophenolate mofetil, and prednisolone. The 1-year incidence of biopsy-proven acute rejection was monitored. Potential biomarkers, namely, CD8CD28, CD4CD57PD1, and CD8CD28 end-stage terminally differentiated memory T cells were measured pretransplantation and posttransplantation and correlated to rejection. Pharmacodynamic monitoring of belatacept was performed by measuring free CD86 on monocytes., Results: The rejection incidence was higher in belatacept-treated than tacrolimus-treated patients: 55% versus 10% (P = 0.006). All 3 graft losses, due to rejection, occurred in the belatacept group. Although 4 of 5 belatacept-treated patients with greater than 35 cells CD8CD28 end-stage terminally differentiated memory T cells/μL rejected, median pretransplant values of the biomarkers did not differ between belatacept-treated rejectors and nonrejectors. In univariable Cox regressions, the studied cell subsets were not associated with rejection-risk. CD86 molecules on circulating monocytes in belatacept-treated patients were saturated at all timepoints., Conclusions: Belatacept-based immunosuppressive therapy resulted in higher and more severe acute rejection compared with tacrolimus-based therapy. This trial did not identify cellular biomarkers predictive of rejection. In addition, the CD28-CD80/86 costimulatory pathway appeared to be sufficiently blocked by belatacept and did not predict rejection.

Background: Belatacept has been associated with an increased acute rejection rate after kidney transplantation. This case report sheds light on the possible immunological mechanisms underlying this phenomenon by analyzing the immunological mechanisms in patient serum, peripheral blood mononuclear cells, rejected kidney tissue, and graft infiltrating cells., Methods: A 61-year-old woman treated with belatacept, who received her first kidney transplant from her husband was admitted with an acute, vascular rejection 56 days after transplantation which necessitated a transplantectomy. Histology and immunohistochemistry were performed on biopsy and explant tissue. CD86 expression on peripheral monocytes was assessed. Using Ficoll density methods, peripheral blood, and graft infiltrating lymphocytes were isolated and phenotyped., Results: The explant showed a vascular rejection (Banff ACR grade III) and a perivascular infiltrate mostly consisting of T cells. No evidence for antibody-mediated rejection was found. In contrast to the peripheral blood monocytes, CD86 was still expressed by part of the mononuclear cells in the explant.Isolated graft cells were mostly CCR7-CD45RO+ effector memory CD4 and CD8 T cells (60-70%). CD28-positive as CD28-negative T cells were present in the explant, showing a great IFN-γ production capacity and expressing granzyme B., Conclusions: We postulate that this glucocorticoid-resistant cellular rejection occurring under belatacept was predominantly mediated by cytotoxic memory T cells, which are less susceptible to costimulatory blockade by belatacept, or resulted from incomplete CD80/86 blockade at the tissue level.

BACKGROUND.: Rabbit antithymocyte globulins (rATGs) are known to convert CD4CD25FoxP3 T cells from healthy individuals to CD4CD25FoxP3 T cells. In this study, we investigated the effect of rATG on the induction of regulatory T cells (Tregs) from blood cells of patients with end-stage renal disease who are candidates for transplantation and rATG-induction therapy. The induced Tregs were analyzed and compared with naturally occurring CD4CD25FoxP3T cells. METHODS.: The CD25 T cells of pretransplant patients (n=7) and healthy controls (n=4) were stimulated with rATG or control rabbit immunoglobulins for 24 hr. The phenotype of induced Tregs was examined by flow cytometry, and their function was studied in the conventional suppression assay. Further characterization was performed by mRNA analyses. RESULTS.: After 24 hr, the percentage of CD4CD25FoxP3CD127 T cells and CD8CD25FoxP3CD127 T cells became higher in the rATG-treated samples compared with the rabbit immunoglobulin-treated samples (P<0.01). The rATG-induced CD25T cells, whether CD4 or CD8 inhibited the allogeneic responses of CD25 effector T cells as vigorously as natural CD25T cells. However, the proportion of FoxP3 within the top 2% rATG-induced CD4CD25T-cells was lower than within the natural CD4CD25T-cells (11%+/-2% vs. 95%+/-5%, P<0.01). The mRNA-expression levels of interleukin-27, interleukin-10, interferon-gamma, perforin, and granzyme B were markedly higher compared with natural CD25T-cells (all P=0.03), whereas CTLA4 (P=0.03), transforming growth factor-beta (P=0.02), and RORgammat (P=0.04) were lower. CONCLUSION.: rATG allows the induction of Tregs from patient peripheral blood mononuclear cell in vitro. In comparison with natural Tregs, the rATG-induced Tregs are phenotypically distinct but have similar regulatory activities. rATG may beneficially contribute to the mechanisms that control alloreactivity.