Minor antigen h60-mediated aplastic anemia is ameliorated by immunosuppression and the infusion of regulatory T cells.
Human bone marrow (BM) failure mediated by the immune system can be modeled in mice. In the present study, infusion of lymph node (LN) cells from C57BL/6 mice into C.B10-H2(b)/LilMcd (C.B10) recipients that are mismatched at multiple minor histocompatibility Ags, including the immunodominant Ag H60, produced fatal aplastic anemia. Declining blood counts correlated with marked expansion and activation of CD8 T cells specific for the immunodominant minor histocompatibility Ag H60. Infusion of LN cells from H60-matched donors did not produce BM failure in C.B10 mice, whereas isolated H60-specific CTL were cytotoxic for normal C.B10 BM cells in vitro. Treatment with the immunosuppressive drug cyclosporine abolished H60-specific T cell expansion and rescued animals from fatal pancytopenia. The development of BM failure was associated with a significant increase in activated CD4+CD25+ T cells that did not express intracellular FoxP3, whereas inclusion of normal CD4+CD25+ regulatory T cells in combination with C57BL/6 LN cells aborted H60-specific T cell expansion and prevented BM destruction. Thus, a single minor histocompatibility Ag H60 mismatch can trigger an immune response leading to massive BM destruction. Immunosuppressive drug treatment or enhancement of regulatory T cell function abrogated this pathophysiology and protected animals from the development of BM failure.
Chen
Jichun
J
Hematology Branch, National Heart, Lung, and Blood Institute, NIH Building 10, Clinical Research Center, 10 Center Drive, Bethesda, MD 20892, USA. chenji@nhlbi.nih.gov
Ellison
Felicia M
FM
Eckhaus
Michael A
MA
Smith
Aleah L
AL
Keyvanfar
Keyvan
K
Calado
Rodrigo T
RT
Young
Neal S
NS
D000741:Anemia, Aplastic / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D000818:Animals; D001772:Blood Cell Count; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D015704:CD4 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016572:Cyclosporine / Q000627:therapeutic use; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D010198:Pancytopenia / Q000188:drug therapy / Q000276:immunology / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000637:transplantation*
D015704:CD4 Antigens; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D015778:Minor Histocompatibility Antigens; C114735:minor H antigen H60; D016572:Cyclosporine