Studies on the survival of histocompatibility-Y antigen (H-Y)-incompatible and skin-specific antigen (Skn)-incompatible skin grafts in mice, as well as those concerned with the survival of cultured parathyroid allografts in rats, indicate that grafts provoke a strong immune response only if they include donor macrophages (or Langerhans cells) or if major histocompatibility complex-compatible macrophages are available to react with cells bearing the foreign antigens.Although a major histocompatibility complex (MHC) restriction with respect to transplantation antigens has been amply and repeatedly demonstrated in vitro (1-7), there is no direct evidence that it plays a role in sensitizing hosts to skin and other organ allografts in vivo (but see refs. 8-10). We provide evidence for such a role. We propose that for a graft to provoke a strong immune response, it is essential that some of its transplantation antigens be expressed on donor macrophages (or cells of this "family") or be presented to the host by macrophages which are MHC-compatible with the graft.Our support for this proposition originates from a series of seemingly unrelated experiments: some concerned with the behavior of skin grafts incompatible with respect to male-specific histocompatibility-Y (H-Y) or skin-specific (Skn) antigens in mice, and others concerned with the behavior of cultured endocrine allografts in rats. The details of the rat experiment are being published elsewhere (11), and most of the data concerning H-Y-incompatible grafts originate from a previous study (12). Thus, although what follows will include data from all of these studies, only the experiments involving Skn will be described in detail.
MATERIALS AND METHODSMale and female A/J (hereafter A; H-2a) and C57BL/6J (hereafter B6; H-2b) mice and their F1 hybrids (B6/A) were used. Tolerance was induced by inoculating B6 mice (less than 24 hr old) with 2 X 107 B6/A spleen and lymph node cells shortly after they had been sublethally irradiated (400 rads of 137Cs irradiation at a dose rate of 98 rads/min). The tolerance-inducing inoculum was prepared in Hanks' balanced salt solution as described (13) and was administered in a standard volume of 0.1 ml of medium through the orbital branch of the anterior facial vein.Neonatal strain A skin grafts, comprising approximately half of the integument of the trunk, were prepared from male or female mice less than 24 hr old. H-Y-incompatible grafts were avoided. Adult grafts (which were of full-thickness body skin) and all original neonatal grafts that were regrafted from one tolerant B6 host to another were 1 cm2. Skin grafting was carried out in accordance with the procedure fully described by Billingham (14). Bandages were removed on the ninth postoperative day, and grafts were evaluated daily for 30 days and at least twice weekly thereafter.To verify that each neonatally treated B6 mouse that rejected a strain A skin graft was nevertheless tolerant of strain A transplantation antigens (i.e., other than Skn antigens), each was su...
Studies on the fate of Skn-incompatible grafts indicate that both the immune response to and the potency of these antigens are influenced by the MHC. Evidence is also presented that strains CBA, C3H, and A possess different Skn antigens.
Studies with mice on the survival of skin grafts incompatible with respect to the histocompatibiiity-Y transplantation antigen or to skin-specific antigens, as well as studies with rats on the fate of cultured parathyroid allografts, provide evidence for major histocompatibility restriction in transplantation immunity. If confirmed, these studies indicate that islet allografts devoid of passenger leukocytes might survive better in major histocompatibility complex incompatible recipients.
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