Comparison of alemtuzumab, anti-thymocyte globulin, and post-transplant cyclophosphamide for graft-versus-host disease and graft-versus-leukemia in murine models

Abstract

Graft-versus-host disease is a major complication after allogeneic hematopoietic stem cell transplantation for hematological malignancies. Immunosuppressive drugs, such as anti-thymocyte globulin, alemtuzumab, and post-transplant cyclophosphamide, have been used to prevent graft-versus-host disease in HLA-mismatched haploidentical hematopoietic stem cell transplantation. Here, we investigated whether these drugs could ameliorate graft-versus-host disease without diminishing the graft-versus-leukemia effect by using a xenogeneic transplanted graft-versus-host disease/graft-versus-leukemia model. Anti-thymocyte globulin treatment diminished graft-versus-host disease symptoms, completely depleted the infiltration of inflammatory cells in the liver and intestine, and led to prolonged survival. By contrast, improvement after post-transplant cyclophosphamide treatment remained minimal. Alemtuzumab treatment modestly prolonged survival despite an apparent decrease of Tregs. In the graft-versus-leukemia model, 1.5 to 2.0 mg/kg of anti-thymocyte globulin and 0.6 to 0.9 mg/kg of alemtuzumab reduced graft-versus-host disease with minimal loss of graft-versus-leukemia effect. Mice treated with 400 mg/kg of post-transplant cyclophosphamide did not develop graft-versus-host disease or leukemia, but it was difficult to evaluate the graft-versus-leukemia effect due to the sensitivity of A20 cells to cyclophosphamide. Although the current settings provide narrow optimal therapeutic windows, further studies are warranted to maximize the benefits of each immunosuppressant.

A Case of Successful Allogeneic Hematopoietic Stem Cell Transplantation in a Severely Underweight Patient with Aplastic Anemia

“…Multiple literature sources have described the curative possibilities and low toxicity of hematopoietic stem cell transplantation for young patients diagnosed with severe aplastic anemia, therefore considering alloSCT the most effective standard of care [ 11 ].…”

“…Furthermore, the infuence of malnutrition in patients receiving alloHSCT, conditioning regimen adaptation, and supportive therapy has not been described in previous literature fndings. Multiple literature sources have described the curative possibilities and low toxicity of hematopoietic stem cell transplantation for young patients diagnosed with severe aplastic anemia, therefore considering alloSCT the most efective standard of care [11].…”

Insights into mechanisms of graft-versus-host disease through humanised mouse models

“…Cell subset manipulation or transfer experiments in humanised mice have provided understanding of the mechanisms of GVHD development by examining the role of specific effector T cell subsets and the role of regulatory subsets including Tregs, MDSCs, tolerogenic DCs and mesenchymal stem cells (MSCs) (as summarised below and in Table 2, 3 and 4). CD4 + and CD8 + T cell subsets readily engraft in immune deficient mice (73)(74)(75)(82)(83)(84)(85)(86)(87)(88)(89), with an increased ratio of human CD4 + :CD8 + T cells indicative of GVHD severity (90), reflecting observations in allogeneic HSCT recipients (91,92). Injection of isolated human T cell subsets into NOG mice has revealed both CD4 + and CD8 + T cells alone can mediate GVHD (93).…”

“…Various studies have used small molecule inhibitors or biologics to study the role of T cells in humanised mice ( Table 2 ). Use of anti-proliferative agents such as cyclophosphamide, azacytidine, anti-thymocyte globulin, alemtezumab [anti-CD52 monoclonal antibody (mAb)], OKT3 (anti-CD3 mAb), CsA, immunoglobulin-like transcript 3 (ILT3)-Fc, IT1208 (anti-CD4 mAb) and anti-CD45RC mAb to reduce GVHD in these models has highlighted the importance of T-cell proliferation in disease progression [ 79 , 89 , 96–100 ]. Moreover, co-administration of human CD83-targeted T cells into humanised mice demonstrated a role for activated CD83 + CD4 + T cells including Th1 and Th2 cells but not Th17 cells, in GVHD progression [ 101 ].…”

Cistanche deserticola polysaccharides alleviate cognitive decline in aging model mice by restoring the gut microbiota-brain axis

“…We then used the immunosuppressive drug, cyclophosphamide [24] to determine the role of inflammation in the beneficial effects of CDPS. Cyclophosphamide-treated CDPS mice (Cy group) showed impaired learning and memory ability, alterations in the gut microbiota composition, and aberrant levels of pro-and anti-inflammatory cytokines in the brain and serum compared to the wild-type and AGING CDPS group mice.…”