Treatment of Autoimmune Disease with Rabbit Anti‐T Lymphocyte Globulin

Abstract

The rabbit anti-T lymphocyte globulins (rATGs) are immune-suppressive anti-T cell agents with beneficial effects in solid organ and hematological transplantation. The present review evaluates the potential mechanisms of rATGs and their impact on pilot and exploratory studies of diffuse cutaneous systemic sclerosis (scleroderma-SSc), inclusion body myositis (IBM), vasculitis, and type 1 diabetes mellitus (T1DM). The rATGs are associated with improvements in well-defined parameters of clinical autoimmunity: insulin usage, tissue inflammation, and systemic organ functions. Meta-analysis of a retrospective database of SSc, N = 196 and two prospective randomized pilot studies; IBM, N = 11 and T1DM, N = 17 shows a two- to ninefold increase in the relative response to treatments with intravenous infusions of rATG. The rATGs deplete T cells and are associated with increases in the percentage of CD25+ T cell subsets. This may underlie the apparent long-lasting immunomodulation associated with these agents. The future optimization of rATG adjunct therapy requires statistically powered-controlled prospective trials of rATG dose-finding and timing of administration. The potential mechanisms of rATGs:depletion of autoreactive T cells, generation CDCD25+Foxp3+ regulatory T cells (Tregs), and the acquisition of regulatory immune cell functions, need to be examined in patients prior to rATG infusion and at time intervals following rATG treatment to identify those mechanisms relevant to the improvement of their clinical outcome.

Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies

“…In order to avoid cost containment measures, we alternated between treatment with Thymoglobulin 2.5 mg/kg/day from day 5 to day 3 before transplant and ATG-F 5 mg/kg/day from day 6 to day 2. Twelve patients were transplanted for AML, the others for undifferentiated acute leukemia [1], lymphoma [9], multiple myeloma [2], chronic myelomonocytic leukemia [3], myelodysplastic syndrome [2], or myelofibrosis [1]. Stem cells came from peripheral blood mononuclear cells for all patients except for one patient in the ATG-F group who received bone marrow.…”

“…Antithymocyte globulins (ATGs) are used as immunomodulatory agents for prevention and treatment of graft-versus-host disease (GvHD) [1] in allogeneic hematopoietic stem cell transplantation (alloHSCT), for prevention and treatment of solid organ graft rejection, for treatment of aplastic anemia, and occasionally for treatment of other autoimmune disorders [2, 3]. These polyclonal immunoglobulins are IgG preparations from rabbits immunized with human thymocytes (Thymoglobulin) or with the T-acute lymphoblastic leukemia cell line Jurkat (ATG-Fresenius, ATG-F) [4].…”

Immunosuppression for liver transplantation

“…A second reason for considering anti-thymocyte globulin use is the notion that lymphocyte depletion could provide an opportunity for “resetting” the immune system, whereby remaining and newly emerging lymphocytes are allowed to engage the transplanted tissue in anticipation that conditions are right for the donor organ to be recognised as self, or that an adaptive regulatory immune response may develop to protect the allograft from destruction. There is some evidence supporting the latter concept, since it has recently been reported that anti-thymocyte globulin treatment results in Treg expansion in vitro and in vivo 69 – 71. So far the effects of thymoglobulin use on Treg development in transplant patients have not been confirmed, but clinical studies are under way to test this concept and to determine whether thymoglobulin can promote organ allograft tolerance.…”

Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis

“…In addition, ATG has known immunomodulatory effects, including induction of adaptive regulatory T cells 96 , that might influence the earliest, and perhaps most critical, stages of immune reconstitution.…”