Monokine induced by interferon-gamma (MIG/CXCL9) is derived from both donor and recipient sources during rejection of class II major histocompatibility complex disparate skin allografts.

Chemokines, including monokine induced by interferon-gamma (Mig/CXCL9), are produced both in allografts and during the direct T-cell infiltration that mediates graft rejection. Neither the specific production nor contribution of allograft donor versus recipient Mig in allograft rejection is currently known. C57BL/6 mice with a targeted deletion in the Mig gene were used as both skin allograft donors and recipients in a class II major histocompatibility complex-mismatched graft model to test the requirement for donor- versus recipient-derived Mig for acute rejection. B6.Mig(-/-) allografts had a 10-day prolonged survival in B6.H-2(bm12) recipients when compared with wild-type C57BL/6 allograft donors, and B6.H-2(bm12) skin allografts had a 5-day prolonged survival in B6.Mig(-/-) versus wild-type recipients. Transplantation of B6.Mig(-/-) skin grafts onto B6.H-2(bm12).Mig(-/-) recipients resulted in further prolonged allograft survival with more than 30% of the grafts surviving longer than 60 days. Prolonged allograft survival was also associated with delayed cellular infiltration into grafts but not with altered T-cell proliferative responses to donor stimulators. Immunohistochemical staining of allograft sections indicated that Mig is produced by both donor- and recipient-derived sources, but Mig from each of these sources appeared in different areas of the allograft tissue. These results therefore demonstrate the synergy of donor- and recipient-derived Mig in promoting T-cell infiltration into allografts.

Skin allograft rejection is suppressed in mice lacking the antiviral enzyme, 2',5'-oligoadenylate-dependent RNase L.

The 2-5A/RNase L system is a regulated RNA decay pathway that mediates some of the antiviral and tumor suppressor activities of the interferons. Previously, we demonstrated that RNase L-null mice have increased susceptibility to viral infections and are partially deficient in induced and spontaneous apoptosis. To determine if RNase L functions in cellular, as well as innate, immunity, skin allograft rejection and contact hypersensitivity (CHS) experiments were performed in RNase L+/+ and RNase L-/- mice. Although no consistent alterations in CHS were found, we did observe a delay of 5 days in the acute rejection of class II major histocompatibility complex (MHC) disparate skin allografts in mice lacking RNase L. Accordingly, histologic examinations of the allografts harvested from RNase L-/- mice revealed a dramatic reduction in inflammatory infiltrates, suggesting a delay in T-cell priming or a deficiency in immune cell trafficking. Results consistent with a proinflammatory role for RNase L extend the known functions of the 2-5A/RNase L system beyond innate immunity into some, but not all, types of cellular immunity.