Minor Antigen H60-Mediated Aplastic Anemia Is Ameliorated by Immunosuppression and the Infusion of Regulatory T Cells

Abstract

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-H2b/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.

Th17 immune responses contribute to the pathophysiology of aplastic anemia

“…25,26,34 At 10 days after LN injection, the proportion of IL-17A positive CD4 ϩ cells in B6 LN-cellinfused animals (15.0% Ϯ 1.1%) was significantly higher (P Ͻ .01) than that in TBI-only controls (6.5% Ϯ 1.3%). Almost no IL-17A positive CD4 ϩ cells were detectable in untreated animals ( Figure 4A upper panels).…”

Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3+ regulatory T cells allows for their purification from expansion cultures

“…Although numerous mechanisms have been proposed to explain the suppressive function of Tregs, none appears to be unifying, and the development of immunomodulating pharmacotherapies has been limited. 9 In mouse models, adoptive immunotherapy with Tregs has been shown to be effective in the prevention of experimental autoimmune encephalomyelitis, 10 type 1 diabetes, 11 SLE,12 autoimmune gastritis, 13 inflammatory bowel disease, 14 aplastic anemia, 15 graft rejection, 16 and GVHD. 17 It is likely that CD4 ϩ FOXP3 ϩ Tregs represent a mixture of thymic-derived and FOXP3 ϩ Tregs that are generated at peripheral sites.…”

Clinical significance and origin of leukocytes that lack HLA-A allele expression in patients with acquired aplastic anemia

“…According to the widely-accepted model of acquired aplastic anemia (AA), cytotoxic T lymphocytes (CTLs) recognize auto-antigens that are presented on hematopoietic stem cells (HSCs) through their class I human leukocyte antigen (HLA) molecules, playing an important role in initiation of the autoimmune reactions that lead to bone marrow (BM) failure [1][2][3]. Several indirect pieces of evidence have been reported in previous studies, such as the accumulation of T cells with particular clonotypes as demonstrated by T-cell receptor analyses [2,4,5], as well as the presence of T-cell clones capable of killing myeloid leukemia cell lines within the BM [6,7].…”

“…Several indirect pieces of evidence have been reported in previous studies, such as the accumulation of T cells with particular clonotypes as demonstrated by T-cell receptor analyses [2,4,5], as well as the presence of T-cell clones capable of killing myeloid leukemia cell lines within the BM [6,7]. However, it is entirely unknown what kind of cells the antigen-specific T cells attack and how these T cells diminish HSCs…”