Induction of suppressive allogeneic regulatory T cells via rabbit antithymocyte polyclonal globulin during homeostatic proliferation in rat kidney transplantation

Abstract

SummaryExperimental studies have shown that rabbit antithymocyte polyclonal globulin (ATG) can expand human CD4+CD25++Foxp3+ cells (Tregs). We investigated the major biological effects of a self-manufactured rabbit polyclonal anti-rat thymoglobulin (rATG) in vitro, as well as its effects on different peripheral T-cell subsets. Moreover, we evaluated the allogeneic suppressive capacity of rATGinduced Tregs in an experimental rat renal transplant model. Our results show that rATG has the capacity to induce apoptosis in T lymphocyte lymphocytes as a primary mechanism of T-cell depletion. Our in vivo studies demonstrated a rapid but transient cellular depletion of the main T cell subsets, directly proportional to the rATG dose used, but not of the effector memory T cells, which required significantly higher rATG doses. After rATG administration, we observed a significant proliferation of Tregs in the peripheral blood of transplanted rats, leading to an increase in the Treg/T effector ratio. Importantly, rATG-induced Tregs displayed a strong donor-specific suppressive capacity when assessed in an antigenspecific allogeneic co-culture. All of these results were associated with better renal graft function in rats that received rATG. Our study shows that rATG has the biological capacity immunomodulatory to promote a regulatory alloimmune milieu during post-transplant homeostatic proliferation.

Regulatory T Cell Infusion Can Enhance Memory T Cell and Alloantibody Responses in Lymphodepleted Nonhuman Primate Heart Allograft Recipients

“…Our goal was to determine the influence of ex vivo –expanded, nonselected Treg infused after ATG‐induced lymphodepletion on heart allograft survival in a clinically relevant NHP model. Our rationale was that (i), compared with the steady state, adoptively transferred functional Treg would be enhanced numerically relative to severely depleted endogenous effector T cells in hosts treated with a lymphocyte‐depleting immunosuppressive regimen and, therefore, better able to regulate alloimmunity and that (ii) incorporation of anti–IL‐6R monoclonal Ab and rapamycin might spare and promote the suppressive function of the infused Treg in an environment that might promote their enrichment during immune reconstitution after ATG administration .…”

The Concerted Action of Multiple Mechanisms to Induce and Sustain Transplant Tolerance

“…A number of investigations demonstrated that the same monoclonal Abs that efficiently eliminate or inhibit effector T cells actually spare Foxp3 + Tregs, in contrast [13][14][15][16][17][18]. Similar observations were reported after treatment with anti-lymphocyte serum or anti-thymocyte globulin [28][29][30][31][32]. Consequently, Treg frequency (but not necessarily absolute numbers) increases in lymphoid organs and in the grafts, thus creating a local Treg-enriched microenvironment amenable to the induction of immune tolerance, and referring to an "immune privileged site" [33].…”

Role of Memory T Cells and Perspectives for Intervention in Organ Transplantation

“…However, several studies have shown that ATG may also play an important role in human Treg survival and expansion both in vitro and in vivo ( 56 , 57 ). An increased ratio of Treg/T effector cells during ATG-induced homeostatic proliferation has been observed in rat kidney transplantation ( 58 ). Although memory T cells are much more resistant to depletion than are naïve T cells, Tregs proliferate to a significantly higher extent than do effector T cells, which suggests a biological preference of ATG for regulation rather than for promoting an effector immune function.…”