Abstract
Blocking the CD28/B7 and/or CD154/CD40 costimulatory pathways promotes long-term allograft survival in many transplant models where CD4(+) T cells are necessary for rejection. When CD8(+) T cells are sufficient to mediate rejection, these approaches fail, resulting in costimulation blockade-resistant rejection. To address this problem we examined the role of lymphotoxin-related molecules in CD8(+) T cell-mediated rejection of murine intestinal allografts. Targeting membrane lymphotoxin by means of a fusion protein, mAb, or genetic mutation inhibited rejection of intestinal allografts by CD8(+) T cells. This effect was associated with decreased monokine induced by IFN-gamma (Mig) and secondary lymphoid chemokine (SLC) gene expression within allografts and spleens respectively. Blocking membrane lymphotoxin did not inhibit rejection mediated by CD4(+) T cells. Combining disruption of membrane lymphotoxin and treatment with CTLA4-Ig inhibited rejection in wild-type mice. These data demonstrate that membrane lymphotoxin is an important regulatory molecule for CD8(+) T cells mediating rejection and suggest a strategy to avoid costimulation blockade-resistant rejection.
Highlights
5 Abbreviations used in this paper: HVEM, herpes virus entry mediator; LTR, lymphotoxin  receptor; mLT, membrane lymphotoxin; LIGHT, a TNF-like molecule homologous to lymphotoxins, showing inducible expression, competing with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes; dendritic cells (DC), dendritic cell; SLC, secondary lymphoid chemokine; MRG, mean rejection grade; Mig, monokine induced by IFN-␥; GVHD, graft-vs-host disease
As an initial approach toward determining the role of lymphotoxin-related molecules in allograft rejection, intestinal allografts were transplanted into LT␣Ϫ/Ϫ recipients
Rejection was completely inhibited when LT␣Ϫ/Ϫ mice were treated with CTLA4-Ig, whereas CTLA4-Ig had no effect on rejection in wild-type recipients (Fig. 1). These data suggest that LT␣-related molecules contribute significantly to the process of allograft rejection and that this effect is predominantly on CD8ϩ T cells
Summary
HVEM, herpes virus entry mediator; LTR, lymphotoxin  receptor; mLT, membrane lymphotoxin; LIGHT, a TNF-like molecule homologous to lymphotoxins, showing inducible expression, competing with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes; DC, dendritic cell; SLC, secondary lymphoid chemokine; MRG, mean rejection grade; Mig, monokine induced by IFN-␥; GVHD, graft-vs-host disease. Recipient survival is not dependent upon the survival of the heterotopic graft, the assessment of transplanted intestines was based upon their histologic appearance
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