STUDIES ON THE INDUCTION OF TOLERANCE OF THE H-Y ANTIGEN IN MICE WITH NEONATAL SKIN GRAFTS

In contrast to the uniform rejection of adult male skin isografts by C57BL/6 females, neonatal male skin isografts are frequently accepted. Moreover, 50% of all females which accept a neonatal male skin graft for 50 days accept a subsequent adult male skin graft as well. This ability of neonatal skin to produce tolerance has been investigated under a variety of experimental conditions. The results indicate: (a) Even when a newborn male skin graft is transplanted concomitantly with an adult graft, it can produce tolerance of the latter although it is less effective in this regard than when transplanted beforehand. (b) The continued exposure of the host to the newborn graft is vitally important in maintaining the unresponsive state; and most females deprived of these grafts for 50 days manifest an immune response when challenged with adult male skin. (c) Newborn male skin isografts raised on adult females are not as antigenic as normal male skin grafts. (d) Occasionally, even a presensitized female can be rendered tolerant by grafting with neonatal male skin. (e) Neonatal male skin grafts are not accepted when transplanted to the spleens of adult females although they may occasionally induce tolerance of a subsequent orthotopic adult male skin graft. The failure of these intrasplenic grafts to survive can be attributed at least partly to their small size since orthotopic grafts of comparable size usually do not survive. (f) Females bearing neonatal male skin grafts are not perceptible cellular chimeras. Because the unresponsive condition induced with neonatal skin is similar to that which results from multiparity, this latter condition has also received attention. In this regard it has been established that unlike the removal of a neonatal male skin isograft, the delayed grafting of isolated females with a previous history of multiparity does not result in many of them manifesting what may be considered an immune response. However, this delay in grafting does seem to impair the tolerance multiparity produces. The results are discussed in relation to other methods of producing tolerance in adult animals

SKIN HOMOGRAFTS: TOLEROGENIC VERSUS IMMUNOGENIC INFLUENCES IN MICE

In strain combinations involving multiple non-H-2 disparities, neonatal skin grafts may survive significantly longer than adult grafts of similar genotype on normal adult hosts, and repeatedly outlive grafts of adult origin on immunosuppressed recipients. Moreover, newborn grafts of long-standing may render their hosts unresponsive to adult skin grafts from the same donor strain. With some H-2-compatible strain combinations in which homozygous neonatal grafts are rejected, F1 hybrid (heterozygous) grafts of similar age not only may survive indefinitely, but also may induce tolerance of subsequent adult parental strain homografts. These tolerogenic and gene dosage effects, although much weaker, can likewise be revealed with H-2-incompatible neonatal skin grafts

THE ROLE OF PASSENGER LEUKOCYTES IN THE ANOMALOUS SURVIVAL OF NEONATAL SKIN GRAFTS IN MICE

The anomalous survival of neonatal C3H skin grafts on CBA mice is correlated with the emigration of passenger leukocytes from the graft vasculature. Thus, newborn homografts whose leukocyte populations are eliminated by X-irradiation or by transient sojourn on an intermediate adult C3H host, do not display prolonged survival. Moreover, the continued presence of the newborn grafts is not requisite to the maintenance of the unresponsive state, an observation consonant with the demonstration that CBA mice bearing long-term neonatal C3H skin grafts are leukocyte chimeras. In contrast, neonatal male C57 skin grafts may persist on C57 females after heavy irradiation of the donor, or after passage on an intermediate adult male host. In addition, tolerance is broken by removal of long-persistant newborn grafts from hitherto unresponsive females, and chimerism is not detectable in female C57 mice tolerant of infant male isografts. Finally, leukocytes of neonatal C3H origin, inoculated subcutaneously into CBA males, may occasionally render these animals unresponsive to subsequent adult C3H skin homografts, whereas those taken from infant C57 males usually sensitize their adult female hosts. Thus, passenger leukocytes are implicated in the extended survival of C3H neonatal homografts on CBA recipients, but not in the persistence of H-Y-incompatible neonatal skin isografts on C57 females