Rabbit antithymocyte globulin (Thymoglobulin(R)) impairs the thymic output of both conventional and regulatory CD4+ T cells after allogeneic hematopoietic stem cell transplantation in adult patients

Abstract

Rabbit antithymocyte globulin-GenzymeTM is used to prevent graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Common disadvantages of treatment are infectious complications. The effects of rabbit antithymocyte globulin-Genzyme TM on thymic function have not been well-studied. Multicolor flow cytometry was used to analyze the kinetics of conventional and regulatory T cells in adult patients treated (n=12) or not treated (n=8) with rabbit antithymocyte globulin-Genzyme TM during the first 6 months after allogeneic hematopoietic stem cell transplantation. Patients treated with rabbit antithymocyte globulin-Genzyme TM had almost undetectable levels of recent thymic emigrants (CD45RA + CD31 + ) of both conventional and regulatory CD4 T cells throughout the 6 months after allogeneic hematopoietic stem cell transplantation whereas CD4 + CD45RA -memory T cells were less affected, but their levels were also significantly lower than in patients not treated with rabbit antithymocyte globulin-Genzyme TM . In vitro, rabbit antithymocyte globulin-Genzyme TM induced apoptosis and cytolysis of human thymocytes, and its cytotoxic effects were greater than those of rabbit antithymocyte globulin-Fresenius TM . Rabbit antithymocyte globulin-Genzyme TM in combination with a conditioning regimen strongly impairs thymic recovery of both conventional and regulatory CD4 + T cells. The sustained depletion of conventional and regulatory CD4 + T cells carries a high risk of both infections and graft-versus-host disease. Our data indicate that patients treated with rabbit antithymocyte globulin-Genzyme TM could benefit from thymus-protective therapies and that trials comparing this product with other rabbit antithymocyte globulin preparations or lymphocyte-depleting compounds would be informative.

Rabbit Anti–T Cell Globulin in Allogeneic Hematopoietic Cell Transplantation

“…Among all immune cells, ATG has the highest affinity for naïve T cells [31], which are enriched for alloreactive T cells [32]. As ATG administration results in severe naïve T lymphocytopenia ( Figure 1) [33][34][35], we hypothesize that many naïve T cells infused with the graft, including alloreactive T cells, are killed by ATG.…”

“…We offer the following 3 hypothetical explanations: (1) GVHD (or its treatment) is a major risk factor for infections, so with lower incidence of GVHD due to ATG, fewer GVHD-associated infections are expected; (2) ATG kills primarily naïve T cells, whereas memory/effector T cells, enriched for T cells against common pathogens, are relatively spared [31,[33][34][35]; and (3) ATG improves the reconstitution of natural killer cells, B cells, and CD8 T cells ( Figure 1) [33].…”

Impact of Immune-Modulatory Drugs on Regulatory T Cell

“…Furthermore, Treg recover faster during immune reconstitution following ATG treatment, contributing to the sustained elevation of Treg/Tconv ratio 34 . However, high-dose ATG impairs thymic generation of Tconv and Treg cells in allogeneic hematopoietic stem cell transplantation 34,35 . ATG therapy may also modulate antigen-specific immune responses by inducing memory-like Treg, as well as other protective T cells such as Th2 and IL-10-producing Tr1 cells 36 .…”

Impact of Serotherapy on Immune Reconstitution and Survival Outcomes After Stem Cell Transplantations in Children: Thymoglobulin Versus Alemtuzumab

“…Alemtuzumab is a humanized monoclonal antibody specific for CD52. In the HSCT setting, both types of serotherapy are used to eliminate T cells, but they also target other cell types, eg, B cells and natural killer (NK) cells [6][7][8][9][10]. ATG and alemtuzumab are considered instrumental in reducing the risk of rejection by suppressing the reaction of host T cells against the graft.…”