THE ALLOANTIBODY NETWORK FOLLOWING INTRATHYMIC IMMUNOMODULATION OF SENSITIZED RAT RECIPIENTS OF CARDIAC ALLOGRAFTS

An intrathymic injection of allogeneic spleen cells (2 x 10(7)) preven ts accelerated (<36 hr) rejection in sensitized LEW rats, and prolongs the survival of LBNF(1) cardiac allografts to about 11 days. This eff ect is donor-specific, x-irradiation-sensitive and thymus-dependent, a nd it does not require adjunctive immunosuppressive therapy. We have r ecently shown that following intrathymic allo-Ag injection, host cell proliferative responses in lymphoid organs are markedly depressed as c ompared with untreated sensitized recipients. Little is known about ho w intrathymic immunomodulation may affect host humoral alloreactivity. In this work, we studied the dynamic interplay between the humoral re sponses, both in the circulation and at the graft site of sensitized h osts. Intrathymic allo-Ag exposure triggered a profound change in the utilization pattern of alloreactive IgM, IgG, and IgG subclasses compa red with recipients receiving syngeneic cells. Administration of allo- Ag into the thymus at the time of sensitization resulted in an earlier and significantly increased systemic production of IgM, as shown by f low cytometry. Subsequently, isotype switching to IgG occurred prematu rely and resulted in elevated levels of IgG1 and IgG2a. Indeed, the ad dition of such allo-Ab enriched serum suppressed the MLR assay in a do se-dependent manner. The binding of Ig to cardiac allografts was analy zed in eluates by Bow cytometry, and by immunohistochemical staining a t day 1 after transplantation. Intragraft IgM and IgG levels were cons istently higher in well-functioning grafts following administration of allo-Ag, as compared with controls. IgG deposits at the graft site co nsisted predominantly of IgG1 and IgG2a, while significant amounts of IgG2b could only be detected in control hosts undergoing accelerated g raft rejection. These data document that intrathymic injection of dono r-specific allo-Ag in sensitized recipients leads to profound alterati ons of the host humoral alloresponses, and that such elevated allo-Ab levels interfere with the Ag reactivity or alloresponsive effector cel ls in vitro. These results support the notion that the pattern of allo -Ab utilization is indicative of the functional status of the alloimmu ne response in the transplant recipient.