Antigen-presenting cells (APC) of mice with chronic graft-versus-host disease (GVHD) cause excessive activation-induced death of T helper cells

Abstract

SUMMARYBoth experimental and clinical forms of chronic GVHD have unique immunological features. The affected animals/individuals suffer from autoimmune disorders such as systemic lupus erythematosus (SLE), and yet they are unable to mount a self MHC-restricted T cell response to foreign antigens. Pathogenesis of the latter phenomenon was investigated in an experimental model of chronic GVHD. Chronic GVHD was induced in 8-10-week-old (B6 × C3H)F 1 mice by tail vein injection of 5 × 10 7 spleen cells of C3H parental strain. The recipients, when tested 3 months later, were unable to mount a T helper (Th) cell response to a randomly selected immunogen, a vaccine of 10 8 killed Mycobacterium vaccae. The animals showed evidence of generalized lymphoid hyperplasia, as indicated by GVH index >1 . 34, and also revealed autoantibodies against erythrocytes and dsDNA, indicating establishment of chronic GVHD. However, mice with chronic GVHD of only 3 weeks duration were able to mount the Th cell response to M. vaccae. Three consecutive immunizations of these mice at 1-week intervals, with the same immunogen, resulted in the mice becoming non-responsive to the antigen. All the three responses tested, namely the DTH, lymphoproliferation and the antibody responses, were adversely affected. The non-responsiveness induced was antigen-specific. Mice receiving two immunizations with M. vaccae responded normally to Salmonella enteritidis. Pulse treatment with cyclosporin A 0 . 5 mg/mouse by the i.p. route, on days 0, 1, 2, 3 and 4 at the time of immunization with M. vaccae on day 1, prevented emergence of non-responsiveness. Based on this evidence, it was concluded that repeated activation of T cells of mice with chronic GVHD induces non-responsiveness. Extent of clonal loss due to activationinduced cell death (AICD) caused by i.p. injection with a superantigen Staphylococcal enterotoxin B (SEB) was investigated in F 1 mice with chronic GVHD. I.p. injection of 25 mg/mouse of SEB induced loss of SEB responding clones in both normal F 1 mice and those having chronic GVHD; however, the extent of loss was much greater in the latter. In vitro antigen-specific proliferation of primed splenic T cells of normal F 1 mice was observed to be quite poor when antigen was presented by APC of mice with chronic GVHD of 3 weeks duration. Proliferation profiles of T cells of normal F 1 mice, in response to stimulation with concanavalin A (Con A) or SEB, were studied, using as APC irradiated spleen cells of normal F 1 mice or of F 1 mice with chronic GVHD of 3 weeks duration. With Con A and APC of normal F 1 mice, peak proliferation was observed at 48 h, which remained at the same level up to 72 h and declined thereafter, possibly due to AICD. With SEB and the normal APC, proliferation progressively peaked at 72 h and declined thereafter. With APC of mice with chronic GVHD, the 48 h proliferative responses of both Con A and SEB were comparable to those caused by APC of normal F 1 mice; however, thereafter the responses declined steeply, suggesting gr...

Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice

“…This difference raised the possibility that transplanted CD8 1 T cells may be eliminated or rendered unresponsive by GVHD. 32,33 We tested this hypothesis by transferring CL4 cells into GVHD mice at 1 of 2 times: at the time of transplantation (CL4 transplant) or 1 day prior to MCMV-HA infection (CL4 infection). Both groups of mice were infected at the same time (ie, 4 weeks posttransplant).…”

The Experimental Model of the Autoimmune Glomerulonephritis Induced by the Chronic Graft versus Host Reaction

“…The mechanism of immunodeficiency has been well studied in case of acute reaction: it's a destruction of the recipient's immune system by donor immune cells. The mechanism of immunosuppression in the chronic form of GVHR remains unclear (Kimura & Gleichmann, 1987;Haridas & Kamat, 1997;Kataoka et al, 2001;Chu & Gress, 2008). In spite of the occurrence of two different variants of chronic GVHR in this model the suppression of primary immune response to T-dependent antigen is observed in all recipients ( Fig.…”

Progression from Acute to Chronic Disease in a Murine Parent-into-F1 Model of Graft-Versus-Host Disease

“…A second model is the injection of C3H splenocytes into (B6 ϫ C3H)F 1 mice. Cell doses of Ͼ2 ϫ 10 7 but Ͻ1 ϫ 10 8 cells result in chronic GVHD and the associated production of autoantibodies, whereas injection of Ն1 ϫ 10 8 cells results in acute GVHD (26). The B6-into-CB6F 1 GVHD differs from these models of GVHD because with the same cell dose B6-into-CB6F 1 mice exhibit acute and chronic GVHD sequentially.…”