Mechanism of action of antithymocyte globulin in the treatment of aplastic anaemia: In vitro evidence for the presence of immunosuppressive mechanism

Abstract

Antithymocyte globulin (ATG) is one of the effective drugs used in the treatment of aplastic anaemia (AA). Although it has been speculated that the mechanism of action of ATG is mediated by its immunosuppressive effect on lymphocytes which might have an inhibitory effect on haemopoietic stem and progenitor cells, no definite evidence of the presence of such a mechanism has been demonstrated. In this study we investigated whether such a mechanism is truly operating in ATG therapy for AA. In five patients who responded to ATG, bone marrow cells were obtained after haematological recovery and CD34-positive cells were separated by immunobeads. Autologous CD34-positive cells were mixed with autologous peripheral CD4- or CD8-positive cells obtained before ATG therapy and after haematological recovery, liquid-cultured for 12 h, and then cultured in methylcellulose for 14 d in the presence of haemopoietic growth factors. In all five cases studied, only the CD8 cells obtained before ATG therapy suppressed the colony forming unit-granulocyte-macrophage (CFU-GM)- and burst forming unit-erythroid (BFU-E)-derived colony formation. This result is definite evidence that one of the mechanisms of action of ATG in AA is an inhibitory effect on CD8-positive cells which have suppressive activity for the growth of haemopoietic progenitor cells.