Progress Toward Transplantation of Tissues in Man

Abstract

(1) Homotransplantation immunity is defective in most patients with agammaglobulinemia and Hodgkin's disease. It parallels the failure of humoral immunity (formation of circulating antibody) in the agammaglobulinemic group and the failure of cellular immunity (delayed hypersensitivity) in the Hodgkin's disease group. (2) Administration of viable spleen cells to newborn mice produces tolerance of skin and endocrine organs from the donor strain, provided the genetic differences are limited. (3) Tolerance was first induced in adult mice by administration of large numbers of C57BL male spleen cells to C57BL female mice, enabling the female recipients to accept skin grafts from the male mice; in most instances, such grafts are ordinarily rejected. Parabiosis of males and females for short periods also produced the same result. (4) Further experiments with parabiosis showed that in adults greater histocompatibility differences could be bridged by pairing of prospective recipient and donor for extended periods. This was accomplished in one combination involving an H-2 histocompatibility difference, (A × C3H)F1 donors and C3H recipients, united for 45 days before surgical separation and subsequent grafting. The experiment involving pairing of this same hybrid with the other parent strain, A, was not successful; most of the animals died before grafting, and the 3 surviving animals which had been kept in parabiosis for 22 days did not accept the hybrid skin grafts. (5) This same H-2 histocompatibility difference was bridged, in adult animals, by multiple injections of donor cells, by a combination of the intravenous and intraperitoneal routes, over a 5 week period. (6) It has been possible, in adult C57BL females, to induce tolerance of skin grafts from C57BL males by repeated administration of a cell-free preparation of male spleen cells. Preliminary results indicate that this type of manipulation may well be successful when greater antigenic differences are present between donor and host. (7) We believe this entire development of tolerance induction in adult mice, particularly with cell-free preparations, has demonstrated that tolerance to skin and tumor grafts, and other forms of specific immunologic negativity, such as that to simple protein antigens and pneumococcal polysaccharides, are not as disparate as they seemed some years ago. (8) Thymectomy of mice in the newborn period greatly depresses homograft immunity; if the thymus is removed completely during the first day of life, the animals, at 30 or 40 days of age, will accept skin from other strains, even those differing at the H-2 locus. That this deficiency extends to heterografts has been demonstrated by Miller, who noted long-term survival of rat skin on neonatally thymectomized mice. (9) Thymectomy in 30 to 40 day old mice also has significant effects if the histocompatibility difference is minor, and particularly if the grafted tissue is tumor rather than skin. Thymectomy in adult animals (both rabbits and mice) also prevents recovery of lymphoid tissue structure and immunologic capacity following x-irradiation. (10) Neonatal thymectomy in rabbits produced a depression of antibody response to bovine serum albumin and T2 phage, but had no apparent effect on homograft immunity. (11) Studies of the ontogeny of lymphoid tissue in the rabbit, mouse, and other species suggest that the thymus is the first lymphoid organ in each species, and that it is the source of lymphoid cells for the peripheral lymphoid tissues at a crucial period in development, differing from species to species, and often quite variable within species (as in rabbits). The thymus apparently also functions as a source of humoral or hormonal substances crucial to immunologic development at this period. (12) Phylogenetic studies have suggested that the development of adaptive immunity—specific circulating antibody, delayed hypersensitivity, and the homograft reaction—is correlated with the development of thymus-like tissue, and that this development takes place in the lower fishes, above the level of the cyclostomes and below the level of the holostean fishes, such as the dogfish (Amia calva).