Equal opportunity targeting in chronic GVHD

Abstract

In this issue of Blood, studies by Rangarajan et al comprehensively analyzing the clonotypic T-cell response provide evidence that the effector T cells that mediate chronic GVHD may have a unique specificity that includes recognition of self.1

Thymic Damage, Impaired Negative Selection, and Development of Chronic Graft-versus-Host Disease Caused by Donor CD4+ and CD8+ T Cells

“…Transplantation of bone marrow (BM) and spleen cells from C57BL/6 donor into lethally irradiated BALB/c recipients has been considered an aGVHD model for more than three decades (21, 41), and autoreactive CD4 + T cells were detected in the recipients early after HCT (42-44). To test whether cGVHD developed in BALB/c recipients transplanted with C57BL/6 donor BM and spleen cells, T and B cell-depleted (TBCD)-BM cells (2.5 ×10 6 ) were injected with or without titrated dose of donor spleen cells (5-1.25 × 10 6 ) into lethally irradiated recipients.…”

Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells in acute GVHD

“…Because the precise antigen specificities of autoreactive effector T cells in cGVHD remain unidentified, 17 we used mOVA as a surrogate self-antigen and tested whether loss of mOVA expression affected central deletion of OVA-specific T cells during aGVHD. We chose the OT-II→RIP-mOVA system because (1) thymic mOVA expression is restricted to mTEC 16 ; (2) TCR selection against mOVA recapitulates physiological tolerance induction to TRA in the thymus medulla 16,[18][19][20][21] ; and (3) a reduction of BLOOD, 23 APRIL 2015 x VOLUME 125, NUMBER 17…”

Immunologic Resolution of Human Chronic Graft-versus-Host Disease

“…Debate on the pathogenesis of chronic GVHD has centered on whether chronic GVHD is a continuation of the pathogenic mechanisms that cause acute GVHD (ie, donor-derived T lymphocytes with specificity for recipient-restricted histocompatibility antigens/cytokines) or a disease of immune dysregulation [1][2][3]. The present demonstration of decreased rTregs in HSCT recipients with active chronic GVHD is similar to the reported deficiencies of rTregs in both adult and pediatric patients with systemic sclerosis, indicating that immune dysregulation may be central to the pathogenesis of both systemic sclerosis and chronic GVHD [24,25].…”

“…Given the clinical similarity of chronic graft-versus-host disease (GVHD) to systemic sclerosis and other autoimmune diseases in humans, the idea that the pathogenesis of chronic GVHD differs from that of acute GVHD has been debated for many years [1][2][3]. It is clear that donor-derived T lymphocytes with specificity for recipient-restricted histocompatibility antigens and the associated cytokines are responsible for the development of acute GVHD; however, the pathogenesis of chronic GVHD is less clear, with recent research focusing on the role of regulatory T lymphocytes (Tregs).…”