Characterization of T-Cell Repertoire of the Bone Marrow in Immune-Mediated Aplastic Anemia: Evidence for the Involvement of Antigen-Driven T-Cell Response in Cyclosporine-Dependent Aplastic Anemia

Abstract

To determine whether the antigen-driven T-cell response is involved in the pathogenesis of aplastic anemia (AA), we examined the complementarity-determining region 3 (CDR3) size distribution of T-cell receptor (TCR) β-chain (BV) subfamilies in the bone marrow (BM) of untreated AA patients. AA patients who did not respond to immunosuppressive therapy and those who obtained unmaintained remission early after cyclosporine (CyA) or antithymocyte globulin (ATG) therapy exhibited essentially a normal CDR3 size pattern. In contrast, five patients who needed continuous administration of CyA to maintain remission exhibited a skewed CDR3 size pattern in a number (>40%) of BV subfamilies suggestive of clonal predominance. The skewing of CDR3 size distribution became less pronounced in one of the CyA-dependent patients when the patient achieved unmaintained remission after a 4-year therapy with CyA, whereas it persisted longer than 7 years in the other patient requiring maintenance therapy. Sequencing of BV15 cDNA for which the CDR3 size pattern exhibited apparent clonal predominance in all CyA-dependent patients showed high homology of the amino acid sequence of the CDR3 between two different patients. These findings indicate that antigen-driven expansion of T cells is involved in the pathogenesis of AA characterized by CyA-dependent recovery of hematopoiesis.

Advances in understanding the pathogenesis of acquired aplastic anaemia

“…The first such methodology, spectratyping analysis, measures the size of the TCR‐β chain complementarity determining region 3 (CDR3) of each of the 24 β chain families. By this analysis a skewed size distribution – suggesting the presence of sizable T cell clones (clonotypes) – was first observed in a group of patients with PNH (Karadimitris et al , ), and then in a larger series of patients with AA (Risitano et al , ), as well as in other studies (Zeng et al , , ). Subsequently, sequence analysis of the TCR‐β chain confirmed the existence of recurring clonotypes in patients with PNH (Gargiulo et al , ) and in children with hepatitis‐associated severe AA (Krell et al , ).…”

Increased expression of TIGIT on CD4+T cells ameliorates immune-mediated bone marrow failure of aplastic anemia

“…AA is regarded an autoimmune disease, in which self-reactive T cells infiltrate into the BM and induce apoptosis of hematopoietic stem/ progenitor cells [Zeng et al, 1999. Recent studies have emphasized the important role of co-inhibitory molecules in autoimmune diseases.…”

Intracellular Fas ligand is elevated in T lymphocytes in severe aplastic anaemia

“…Although immune‐mediated suppression of haemopoiesis is considered the most important mechanism in the development of idiopathic AA, understanding of the role of T cells in the pathogenesis of BM failure is elusive and potential autoantigens or target antigens of bacterial or viral origin remain unidentified (Young, 1996). This is largely owing to the heterogeneity of the disease at presentation and the fact that many experimental findings on abnormalities in the T‐cell compartment are not common to all AA patients (Maciejewski et al , 1994; Manz et al , 1997; Zeng et al , 1999). Recent studies suggest that excess apoptosis may represent an important factor contributing to stem cell deficiency in AA.…”