Dendritic Cells Secrete the Immunosuppressive HLA-G Molecule upon CTLA4-Ig Treatment: Implication in Human Renal Transplant Acceptance

Abstract

CTLA4-Ig (Belatacept) is a new recombinant molecule that interferes with the signal of T lymphocyte activation and prevents acute rejection after renal transplantation. HLA-G acts as a naturally tolerogenic molecule in humans. In this study, we analyzed whether HLA-G contributes to CTLA4-Ig-mediated graft acceptance. Our results demonstrate that patients treated with CTLA4-Ig displayed significantly higher soluble HLA-G (sHLA-G) plasma concentrations (72 ± 14 ng/ml) than patients treated with calcineurin inhibitors (5 ± 1 ng/ml) or healthy donors (5 ± 5 ng/ml). Notably, sHLA-G purified from plasma of CTLA4-Ig-treated patients was biologically active as it inhibited allogeneic T cell proliferation in vitro. Dendritic cells (DC) were identified as one of the cellular sources of sHLA-G in CTLA4-Ig-treated patients. Supporting this observation, we showed that DC generated in vitro in presence of CTLA4-Ig released sHLA-G in response to allostimulation. These CTLA4-Ig-treated DC acted as tolerogenic APC through sHLA-G secretion as they suppressed T cell alloproliferation, which could be restored by using a neutralizing anti-HLA-G Ab. These data define a novel pathway by which CTLA4-Ig immunomodulates allogenic response through posttranscriptional regulation of HLA-G expression in DC. CTLA4-Ig-mediated HLA-G release appears as a critical factor in T cell alloresponse inhibition, thereby contributing to the immunosuppressive effect and graft acceptance.

The role of HLA-G in immunity and hematopoiesis

“…In this regard, soluble HLA-G plasma levels were found to be enhanced after cyclosporine or tacrolimus administration in some heart transplant patients [51]. The effect of the immunosuppressive therapy on HLA-G expression was supported by recent results showing augmented HLA-G plasma levels in kidney transplant patients treated with the CTLA4-Ig fusion protein (Belatacept) [52]. This therapeutic agent is associated with better graft function and survival.…”

“…Considering the immunological role of HLA-G, many studies have demonstrated that HLA-G is a good prognostic factor for engraftment, not only in the context of pregnancy in which the fetus can be considered a semiallogeneic transplant but also in allogeneic transplants (heart, liver-kidney, kidney and lung transplants) [27,40,52,163]. Moreover, high HLA-G levels were recently associated with poor prognosis in various cancers [4,77,164,165].…”

“…Definition of the mechanism by which such therapy promotes HLA-G expression showed that dendritic cells secrete soluble HLA-G upon CTLA4-Ig treatment. CTLA4-Igtreated DC acquire tolerogenic properties as they suppress T cell proliferation through soluble HLA-G release [52].…”

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

“…83 However, several experimental studies have shown the role of reverse signaling of CD80/CD86 in CTLA4-mediated coinhibition. 84 CTLA4-Ig binds to CD80/ CD86 molecules on dendritic cells and promotes the induction of the immunomodulatory enzyme indoleamine 2,3 dioxygenase 85,86 and the tolerogenic molecule HLA-G. 87 Experimental data suggest that reverse signaling of CD80/ CD86 also exists in B cells. 88,89 It is, therefore, tempting to speculate that, when belatacept binds to CD80/CD86, it directly influences the B cell fate.…”

The tolerogenic interplay(s) among HLA-G, myeloid APCs, and regulatory cells

“…32 Immunotolerogenic stimuli, such as CTLA4-Ig, may further enhance HLA-G up-regulation. 36 Interestingly, the tryptophan catabolyzing enzyme indoleamine 2 3-dioxygenase (IDO) was shown to differentially modulate HLA-G expression in monocytes and myeloid DCs: IDO blocked HLA-G cell-surface expression on monocytes, 37 but it induced HLA-G expression and shedding in myeloid DCs. 38 IDO is known to be involved in the generation of tolerogenic microenvironments by tryptophan depletion and in the generation of Tregs.…”