Graft-versus-host disease in recipients of grafts from natural killer T cell-deficient (Jalpha281(-/-)) donors.

Valpha14i natural killer T cells (NKT cells) are a CD1-restricted subset of NKT cells that express an invariable Valpha14+ Jalpha281+ alphabeta T-cell receptor. To determine whether the absence of Valpha14i NKT cells from the graft affects the development of acute GVHD, we induced GVH reactions using Jalpha281(-/-) mice as donors in the C57BL/6-->(C57BL/6 x DBA/2)F1-hybrid strain combination. Recipients of grafts from Jalpha281(-/-) donors were not protected from either the morbidity or the severe wasting syndrome associated with the development of acute GVHD, but the concentrations of some T helper 1 (Th1) and Th2 cytokines were different from those seen in recipients of grafts from wild-type donors. Interferon-gamma was seen earlier (day 4) in recipients of grafts from Jalpha281(-/-) donors but did not reach the concentrations seen in recipients of grafts from wild-type donors on day 8 (P < 0.02). On day 8, the amount of tumour necrosis factor-alpha released into the serum following the injection of a small amount of lipopolysaccharide was lower in recipients of grafts from Jalpha281(-/-) donors (P < 0.02). The amount of interleukin (IL)-5 was also lower in recipients of grafts from Jalpha281(-/-) donors, when compared to the concentration seen in recipients of grafts from wild-type donors (P < 0.002). IL-13 was seen in recipients of grafts from Jalpha281(-/-) donors but not in recipients of grafts from wild-type donors. Our findings show that the absence of donor Valpha14i NKT cells is associated with lower concentrations of some Th1 cytokines. We also observed higher IL-13 concentrations and lower IL-5 concentrations in recipients of grafts from Jalpha281(-/-) donors indicating a variable effect on Th2 cytokine production.

Effect of recombinant human keratinocyte growth factor (rHuKGF) on the immunopathogenesis of intestinal graft-vs.-host disease induced without a preconditioning regimen.

We studied the effect of rHuKGF on acute, lethal graft- vs.-host disease (GVHD) in the C57BL/6-->(C57BL/6 X DBA/2)F(1)-hybrid model. rHuKGF-treated recipients did not develop intestinal GVHD despite elevated levels of intestinal NO and TNF alpha, did not develop endotoxemia, and did not die. LPS augmented serum TNF alpha release and intestinal NO production, but did not induce intestinal epithelial cell apoptosis, a phenomenon associated with acute GVHD. These data suggest that KGF prevents the development of acute lethal GVHD by protecting epithelial cell injury mediated by TNF-alpha, NO, and other potential cytotoxic factors. We noted a moderate reduction in intestinal KGFR mRNA expression in untreated GVH mice on day 8, when IFN-gamma mRNA levels were highest. This reduction in KGFR mRNA levels was not seen in recipients of IFN-gamma gene knockout grafts, suggesting that IFN-gamma may be involved in reducing KGFR mRNA expression in the intestine. A similar reduction in intestinal KGFR mRNA expression was also seen in rHuKGF-treated recipients, suggesting that rHuKGF does not mediate its protective effect by maintaining KGFR at control levels. KGF-treatment also redirected the cytokine response in acute GVH mice from Th1 to a mixed pattern of both Th1 and Th2 cytokines. This was associated with histopathologic changes resembling chronic GVHD.

Murine graft-versus-host disease induced using interferon-gamma-deficient grafts features antibodies to double-stranded DNA, T helper 2-type cytokines and hypereosinophilia.

Acute, lethal graft-versus-host disease (GvHD) develops in B6D2F1 hybrid recipients of wild-type, C57BL/6, parental strain grafts; however, when interferon-gamma (IFN-gamma) gene knockout (gko) donors are used, the disease is prolonged and associated with a higher level of engraftment, particularly of T cells. Lesions containing large, mixed cellular infiltrates develop in the skin, liver, pancreas, salivary gland, lung and kidney. In our current study, we wished to determine whether GvHD features a preponderance of T helper 2 (Th2) cytokines in the absence of donor-derived IFN-gamma, and whether autoantibody production, commonly associated with chronic GvHD, also occurs. Because mitogen responsiveness is consistently suppressed in mice with acute GvHD, we wished to measure this response in recipients of IFN-gamma gko grafts. Our findings indicate that spleen cells from the latter produce interleukin (IL)-4, IL-5 and IL-13 in culture, but respond poorly to concanavalin A (Con A) and lipopolysaccharide (LPS). Their sera contain anti-nuclear antibodies (ANA), some of which are specific for double-stranded (ds)DNA and are predominantly immunoglobulin (Ig)M and IgG1. We also noted the presence of numerous eosinophils in the infiltrates developing within the target organs. In some respects, this syndrome bears resemblance to both systemic lupus erythematosus (SLE) and chronic GvHD. However, histological evidence of glomerulonephritis is lacking and proteinuria fails to develop in recipients of IFN-gamma gko grafts, suggesting that IFN-gamma may be necessary for the development of lupus nephritis. On a broader scope, our findings underscore the importance of IFN-gamma in the pathogenetic mechanism of GvHD, and demonstrate that the absence of this cytokine promotes the development of chronic GvHD and autoimmunity.