DISSOCIATION OF HOMOGRAFT RESPONSE TO ALLOGENEIC VERSUS XENOGENEIC SKIN GRAFTS IN IRRADIATED MICE

Lethally x-irradiated (C3H x DBA/2)F(1) mice were protected with syngeneic (isogenic) bone marrow and/ or prior treatment with urethan and skin grafted at various times after irradiation. The ability to reject a first-set xenogeneic (heterologous) skin graft with normal vigor returned within 92 days; the first-set response to allogeneic (homologous) grafts was still impaired 350 days after irradiation.     

Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice

Neonatal thymectomy of mice, when no ectopic thymus existed, constantly resulted in developmental arrest of the ovary but not of the testis; it also caused sterility in the female. The ovaries of thymectomized mice were extremely small and were characterized by absence of follicles and corpora lutea. Such an ovarian dysgenesia was observed when the mice were thymectomized at 3 days of age, but not at 7 days or later; it was prevented by thymus grafting.     

Lymphocytes from thymectomized rats: immunologic, proliferative, and metabolic properties

Thoracic duct lymphocytes from neonatally thymectomized Lewis rats fail to produce runt disease in newborn Brown Norway rats when injected with up to ten times the number of normal lymphocytes needed to cause runting. The immunologically deficient lymphocytes appear, however, to confer tolerance, and at least some enlarge and divide when stimulated in vitro with phytohemagglutinin, or xenogeneic or allogeneic cells. Small lymphocytes from thymectomized animals have defective RNA metabolism as judged by a marked impairment in their ability to incorporate uridine-5-H(3) or cytidine-H(3) in vitro.     

Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice

Athymic-nude (nu/nu) mice and normal (nu/+) mice showed no differences in either latent period or incidence of local sarcomas or lung adenomas within 120 days after administration of 3-methylcholanthrene at birth. However, nu/nu mice were incapable of rejecting allogeneic skin grafts for the duration of the experiment. These results argue against an active role of thymus-dependent immunity as a surveillance mechanism preventing tumor development.     

Delayed hypersensitivity: bone marrow as the source of cells in delayed skin reactions

Adult Lewis rats were thymectomized, irradiated, and restored with bone marrow from allogeneic (or F(1)) donors. They were passively sensitized to tuberculin by a subsequent transfer of Lewis lymph node cells and were given intradermal skin tests with tuberculoprotein. In 24-hour skin reactions the majority of cells, in successive experiments, were shown to be allogeneic (or F(1)) with the use of isoantibody against the antigens of the transplanted marrow cells and by the indirect fluorescent antibody technique. Our results demonstrate that the non-specific cells making up a large proportion of the infiltrating elements in tuberculin skin reactions probably originate in the bone marrow.     

THYMECTOMY: PROLONGATION OF IMMUNOLOGICAL TOLERANCE IN THE ADULT MOUSE

The loss of acquired immunological tolerance of mice to bovine gamma globulin depended on the presence of the thymus. Mice were repeatedly injected with bovine gamma-globulin from birth until the age of 5 to 10 weeks and then thymectomized or sham operated. After 130 to 160 days without antigen, an accelerated (immune) disappearance of I(125) bovine gamma-globulin could be uniformly induced in controls while thymectomized mice remained tolerant. Adult thymectomized mice made tolerant by a single injection of bovine gamma-globulin lost tolerance more slowly than sham-operated controls.     

Drug-induced tolerance for skin allografts across the H-2 barrier in adult mice

Mice treated with methylhydrazine derivatives for 3 to 4 weeks before the transplantation showed markedly prolonged survival times for allogeneic skin grafts differing at the H-2 histocompatibility locus. Presumably permanent tolerance was induced in about 20 to 30 percent of the mice when the drug treatment was combined with a single injection of additional donor antigen. The tolerance persists without further drug treatment and is specific for donor tissue.     

Neonatal thymectomy results in a repertoire enriched in T cells deleted in adult thymus

In B6AF1 mice, T lymphocytes that use the V beta 11-positive (and not V beta 6-positive or V beta 8-positive) segment in their receptor for antigen are greatly reduced in the thymus and peripheral lymphoid tissues, most likely as a result of clonal deletion. The relative number of V beta 11-positive cells in adult lymph nodes was ten times as high in B6AF1 mice thymectomized 1 to 4 days after birth as in normal mice. Moreover, for the first 10 days of life of B6AF1 mice, mature V beta 11-positive T cells were readily detected in the thymus and spleen. Thus neonatal thymectomy results in the maintenance of the receptor repertoire of early postnatal life, and this correlates with the subsequent development of organ-specific autoimmune diseases.     

Local recognition of histocompatibility differences in skin grafts

Studies in rabbits of skin grafts tagged with tritiated thymidine indicate a greater proliferation of endothelial cells and fibroblasts at the site of an allograft than at that of an autograft as early as the first day after grafting. It appears, therefore, that allogeneic differences can be recognized and responded to locally almost at once. Labeled nuclear material is found to be transferred from the epithelial cells of skin grafts to host cells of the adjacent tissues. A mechanism therefore exists which might effect a local transfer of information on histocompatibility differences.     

Immunization with skin isografts taken from tolerant mice

Skin isografts from mice that were immunologically tolerant to allogeneic tissue had the ability to immunize isogeneic recipients against subsequent skin allografts. The immunizing isografts showed no gross signs of rejection themselves and appeared to be only the vehicles for transplantation antigen. It seems likely that allogeneic leukocytes derived from the spleen and bone marrow cells used to confer tolerance were contained in the skin of the tolerant mice and were transferred by the skin isografts in sufficient numbers to stimulate transplantation immunity.     

Influence of SHIP on the NK repertoire and allogeneic bone marrow transplantation

Natural killer cell (NK) receptors for major histocompatibility complex (MHC) class I influence engraftment and graft-versus-tumor effects after allogeneic bone marrow transplantation. We find that SH2-containing inositol phosphatase (SHIP) influences the repertoire of NK receptors. In adult SHIP-/- mice, the NK compartment is dominated by cells that express two inhibitory receptors capable of binding either self or allogeneic MHC ligands. This promiscuous repertoire has significant functional consequences, because SHIP-/- mice fail to reject fully mismatched allogeneic marrow grafts and show enhanced survival after such transplants. Thus, SHIP plays an important role in two processes that limit the success of allogeneic marrow transplantation: graft rejection and graft-versus-host disease.     

Male-specific antigen: modification of potency by the H-2 locus in mice

Skin grafts from C57BL/10 (B10) male mice survive significantly longer than do B10.BR male skin grafts on (B10 x X B10.BR)F(1) females. This indicates that the H-2 locus influences the potency of the male-specific antigen in mice.     

Leukemia virus activation during homograft rejection

Activation of murine leukemia viruses, as detected by the mixed culture cytopathogenicity (XC) assay, followed the transplantation of A/J skin onto immunosuppressed BALB/c mice. Virus was found in most of the mice receiving both skin grafts and antilymphocyte serum, but not in animals receiving either the serum alone, skin graft alone, or no treatment.     

Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants

T cells that accompany allogeneic hematopoietic grafts for treating leukemia enhance engraftment and mediate the graft-versus-leukemia effect. Unfortunately, alloreactive T cells also cause graft-versus-host disease (GVHD). T cell depletion prevents GVHD but increases the risk of graft rejection and leukemic relapse. In human transplants, we show that donor-versus-recipient natural killer (NK)-cell alloreactivity could eliminate leukemia relapse and graft rejection and protect patients against GVHD. In mice, the pretransplant infusion of alloreactive NK cells obviated the need for high-intensity conditioning and reduced GVHD. NK cell alloreactivity may thus provide a powerful tool for enhancing the efficacy and safety of allogeneic hematopoietic transplantation.     

Lymphocytic Choriomeningitis Infection in Neonataily Thymectomized Mice Bearing Diffusion Chambers Containing Thymus

Normal, nonoperated Swiss mice which had been inoculated intracerebrally with lymphocytic choriomeningitis virus showed a 100-percent mortality within 8 days after virus challenge. Neonatally thymectomized mice, with or without empty intraperitoneal diffusion chambers, were protected from the lethal effects of the virus, with no animals dying within 14 days after inoculation. Cell-tight Millipore diffusion chambers containing newborn thymic tissue, implanted intraperitoneally into neonatally thymectomized mice, restored the susceptibility of 52 percent of these mice to the lethality of the virus infection. The percentage restoration with subcutaneous thymic grafting was similar. A humoral mechanism of action of the tissue in the chamber is proposed.     

Genetic background and expressivity of histocompatibility genes

A difference in the reactivity of F(1) hybrid female mice to skin grafts from male donors of each of their parental strains suggests that the genetic background can influence the efficacy of the Y antigen to elicit rejection of the graft.     

Identification of the miniature pig inbred line by skin allograft

Skin grafting has been used as one of the most reliable tests to determine the genetic stability of laboratory animal such as mice and rats inbred line, but no identification of swine inbred lines by skin grafting has been reported. At present, Wuzhishan miniature pig(WZSP) inbred line has acquired the F24 individuals in China. In order to verify whether WZSP inbred line had been cultivated successfully, allogeneic skin grafts and related research were performed on F20 individuals of WZSP inbreeding population, compared with a control group of autologous transplantation. We observed the transplant recipients' wounds, detected peripheral blood-related indicators interleukin-2, 4 and 10, CD4+ and CD8+ lymphocytes, and conducted hematoxylin-eosin(HE) and Masson's staining of skin to judge whether the immune rejection reactions occurred within 28 days after transplantation. Chr. 7 genomic heterozygosity of 48 WZSP individuals from F20 to F22 was analyzed by high-density single nucleotide polymorphism(SNP) chips(60 000 SNPs). The result showed that there were no significant differences in graft skin, the plasma interleukin-2, 4, 10, CD4+ and CD8+, HE and Masson's staining results between the allograft and autograft groups, and no immune rejection occurred on the allograft group. We found that 11 genes in Chr. 7 of major histocompatibility complex(MHC) I and MHC II were homozygous which confirmed that immune antibody of the allograft and autograft groups were highly identical and also provided a theoretical basis to no immune rejection occurred on the allograft in the inbred WZSP. The result proved that the WZSP inbred line had been cultivated successfully for the first time in the world. The test methods also provide a scientific basis for the identification of swine and mammal inbred lines.     

Prevention of allogeneic bone marrow graft rejection by H-2 transgene in donor mice

Rejection of bone marrow grafts in irradiated mice is mediated by natural killer (NK) cells and is controlled by genes linked to the major histocompatibility complex (MHC). It has, however, not been possible to identify the genes or their products. An MHC class I (Dd) transgene introduced in C57BL donors prevented the rejection of their bone marrow by NK cells in irradiated allogeneic and F1 hybrid mice expressing the Dd gene. Conversely, H-2Dd transgenic C57BL recipients acquired the ability to reject bone marrow from C57BL donors but not from H-2Dd transgenic C57BL donors. These results provide formal evidence that NK cells are part of a system capable of rejecting cells because they lack normal genes of the host type, in contrast to T cells, which recognize cells that contain abnormal or novel sequences of non-host type.     

Trophoblast antigenicity demonstrated by altered challenge graft survival

Adult C57BL/6J male mice received either a primary ectopic transplant or a primary and a challenge ectopic transplant of trophoblast tissue obtained from the ectoplacental cones of 7(1/2)-day-old C3H/HeJ x C3H/HeJ embryos. Gross and histologic examinations of these grafts at 5, 7, and 12 days of growth indicated that the challenge grafts were inhibited in growth; there were a smaller percentage of grossly successful grafts, smaller hemorrhagic reactions, fewer viable cells at all stages of growth, and better host containment of the colony. The evidence indicates that exposure to pure trophoblast alters an animal's subsequent reaction to grafts syngeneic with the original trophoblast and can best be explained as evidence of immunologic sensitization of the host.     

Thymus-dependent lymphocytes: destruction by lymphocytic choriomeningitis virus

Selective destruction of small lymphocytes in the thymusdependent areas of lymph nodes and thymocytes was observed in mice infected with lymphocytic choriomeningitis virus. These changes were clearly evident in lymphoid and splenic tissue 3 days after infection and in the thymus by day 7. The destructive changes paralleled growth of the virus in these organs. The findings show that infection with lymphocytic choriomeningitis virus can temporarily cause the equivalent effect of neonatal thymectomy, that is, a "viral thymectomy," which appears to be related to the ability of this virus to cause persistent infection.