CD20, AIF-1, and TGF-β in graft-versus-host disease: a study of mRNA expression in histologically matched skin biopsies

Abstract

Graft-versus-host disease is the leading cause of non-relapse mortality after allogeneic bone marrow transplantation. The cell-mediated immune mechanisms that underlie the pathogenesis of graft-versus-host disease remain unclear. In this study, 47 skin biopsies representing graft-versus-host disease grades 0–III, lichenoid, and sclerodermoid were included from 31 allogeneic bone marrow transplantation recipients. RNA from paraffin-embedded tissue was harvested. Transcript levels of the following markers were assessed and correlated with grade and survival: CD3, CD20, FoxP3, IL-17, γ-interferon (IFN-γ), transforming growth factor-β (TGF-β), IL-6, connective tissue growth factor (CTGF), allograft inflammatory factor-1(AIF-1), and IL-13. Levels of three markers significantly correlated with the length of survival (TGF-β, correlation coefficient −20.8, P = 0.016; AIF-1, 13.2, P = 0.016; and CD20, 66, P = 0.027). CD20 expression was limited to lichenoid cases. Levels of TGF-β, AIF-1, and IFN-γ appeared to correlate with histological progression, but did not reach statistical significance. Expression of FoxP3 correlated with worse survival, and approached statistical significance (P = 0.053). Two potential mechanistic pathways were identified: the ‘scleroderma’ group (AIF-1 and TGF-β) and the ‘B-cell’ group (CD20). Transcript levels of these markers were implicated in the progression from acute to chronic disease, and also correlated significantly with the duration of survival. Identification of these three markers may direct therapy selection with targeted agents, including the use of rituximab when B-lymphocytes are implicated.

Pleiotropic Effects of Transforming Growth Factor-β in Hematopoietic Stem-Cell Transplantation

“…TGFβ mRNA transcripts were found to be elevated in skin biopsies of patients experiencing cutaneous GVHD (10). Additionally, high dose irradiation can stimulate overproduction of TGFβ1 in the human lung (11).…”

Graft-versus-host disease

“…86 In a small study, evaluation of RNA from paraffinembedded tissues harvested from sclerotic skin revealed increased transcript levels of allograft inflammatory factor-1 (AIF-1) and transforming growth factor-beta, whereas lesions resembling lichen planus contained higher levels of CD20 1 cells. 96 …”

Equal opportunity targeting in chronic GVHD

“…2 The onset of this posttransplantation complication, termed acute GVHD, is characterized by cutaneous eruptions, rash, and purpuric lesions in the skin along with infiltrates of T cells into the epidermis. 3 Pathologic changes consistent with an acute inflammatory response can also be detected in the gastrointestinal tract and the liver during acute GVHD.…”

“…Recent studies suggest that both acute and chronic GVHD have distinct cytokine responses. 3 In this regard, recent studies also suggest that the effector T cells shift from a type 1 profile to a type 2 profile during the transition from acute to chronic GVHD. 8 This transition appears to be the result of a breakdown in self-tolerance.…”

“…2 Interestingly, chronic GVHD is characterized by fibrosis and sclerosis along with T cell-mediated destruction of the dermis. 2,3 The pathologic changes in chronic GVHD, in fact, are similar to autoimmune diseases such as Sjogren syndrome, lichen planus, and scleroderma. 2,3 There has been an ongoing debate about whether chronic GVHD is truly an autoimmune disease and whether this post-BMT complication is mediated by alloreactive or autoreactive T cells.…”