Alloimmune Response Results in Expansion of Autoreactive Donor CD4+ T Cells in Transplants That Can Mediate Chronic Graft-versus-Host Disease

Abstract

Chronic graft versus host disease (cGVHD) is considered an autoimmune-like disease mediated by donor CD4+ T cells, but the origin of the autoreactive T cells is still controversial. Here, we report that transplantation of DBA/2 donor spleen cells into thymectomized MHC-matched allogeneic BALB/c recipients induced autoimmune-like cGVHD, although not in control syngeneic DBA/2 recipients. The donor-type CD4+ T cells from the former but not the latter recipients induced autoimmune-like manifestations in secondary allogeneic BALB/c as well as syngeneic DBA/2 recipients. Transfer of donor-type CD4+ T cells from secondary DBA/2 recipients with disease into syngeneic donor-type or allogeneic host-type tertiary recipients propagated autoimmune-like manifestations in both. Furthermore, TCR spectratyping revealed that the clonal expansion of the autoreactive CD4+ T cells in cGVHD recipients was initiated by alloimmune response. Finally, hybridoma CD4+ T clones derived from DBA/2 recipients with disease proliferated similarly to stimulation by syngeneic donor-type or allogeneic host-type DCs. These results demonstrate that the autoimmune-like manifestations in cGVHD can be mediated by a population of donor CD4+ T cells in transplants that simultaneously recognize antigens presented by both donor and host APCs.

Chemokine-mediated tissue recruitment of CXCR3+ CD4+ T cells plays a major role in the pathogenesis of chronic GVHD

“…Many clinical features resemble disorders such as scleroderma or systemic lupus erythematosus, and this has led to suggestions that both allo-immune and auto-immune T-cell recognition may contribute to the disease pathogenesis. [20][21][22][23] In the present study, we found that the IFN␥-inducible chemokines CXCL9, CXCL10, and CXCL11 are increased by up to 3-fold in the serum of patients with cGVHD of the skin. This provides an insight into the pathogenesis of cGVHD, for which there is a paucity of studies investigating the mechanism of this devastating condition.…”

Anti–IL-12/23 p40 Antibody Attenuates Experimental Chronic Graft-versus-Host Disease via Suppression of IFN-γ/IL-17–Producing Cells

“…Liver slides were scored based on bile duct injury and inflammation (0-4 for each category), and the maximum score was 8 (33). Salivary slides were scored on mononuclear cell infiltration and follicular destruction, and the maximum score was 4 (34). All slides were scored by a pathologist (T.T.)…”

Antibodies from donor B cells perpetuate cutaneous chronic graft-versus-host disease in mice

“…All experiments were approved by the City of Hope institutional animal care and use committee. Induction and assessment of graft-versus-host disease (GVHD), antibodies, flow cytometry analysis and sorting, histopathology and histoimmunofluoresent staining, real-time polymerase chain reaction, and statistical analysis are described in previous publications 15,16,24 and in supplemental Methods (available on the Blood Web site). Figure 1A-B).…”