Rejection Of Male Skin Grafts Research Articles

A continuous infusion of a minor histocompatibility antigen–immunodominant peptide induces a delay of male skin graft rejection

We previously reported that an inhibition of antigen-specific Interferon-γ release and cytotoxicity occurs after a continuous infusion of an HY immunodominant peptide although this treatment is not able to cause a significant delay of male skin grafts rejection. In vivo administration of high doses of an HY peptide, through mini-osmotic pumps, in naïve female mice was used to study the effects on the male skin grafts rejection. A continuous infusion of 1 mg of an HY peptide induces a significant delay of male skin graft rejection. In vitro HY-specific Interferon-γ release was inhibited adding peptide-specific suppressor cells: the ability to inhibit Interferon-γ release was evident when two HY peptides were present on the same dendritic cells indicating that the suppressor cells exert “linked-suppression”. The phenotype of the suppressor cells is CD8 +CD28 − and these cells express more CD62 ligand and FOXP3 than controls. Suppressor cells were able to cause a significant delay of rejection of male skin grafts when injected in naive female mice. The inhibitory effects of these suppressor cells seem to be due to the impairment of antigen presentation; down-regulation of B7 molecules on dendritic cells occurred. Taken all together, our data demonstrate that a continuous infusion of an immunodominant HY peptide induces a T CD8 suppressor subset able to inhibit immune responses to male tissues and cells.

Induced peripheral regulatory T cells: The family grows larger

In order to control immune reactions and to prevent autoimmunity, the immune system relies on a multitude of regulatory T cells (Treg). Most work in this field has focussed on Treg of the CD4(+) T cell subset because of the central role CD4(+) T cells play as initiators and regulators of immune responses. One discovery of particular importance was the identification of naturally occurring CD4(+)CD25(+) Treg that arise in the thymus and express the transcription factor Foxp3; however, Treg can also be induced in the periphery after immune activation. A paper in this issue of the European Journal of Immunology identifies a novel type of induced murine CD8(+) Treg that arise in TCR HY transgenic female mice after injection of MHC class I tetramers loaded with HY peptide. These Treg prevent subsequent rejection of male skin grafts suggesting that their manipulation may represent a new way of improving graft rejections against minor histocompatibility barriers.

APPARENT LACK OF H-Y-SPECIFIC SUPPRESSOR CELLS IN FEMALE MICE GIVEN MALE SPLEEN CELLS INTRAVENOUSLY

Mice given a pretransplant i.v. infusion of spleen cells from donors incompatible with the recipients with respect to individual minor H antigens exhibit a delayed rejection of skin grafts from these incompatible donors. Attempts were made to detect suppressor T cells, possibly induced by the i.v. infusion of donor cells, among spleen cells from female mice made hyporesponsive to H-Y antigen by an i.v. infusion of male spleen cells. When transferred to nonimmune immunocompetent mice, lymphoid cells from hyporesponsive females delayed the rejection of male skin grafts only slightly. Similar results were obtained when putative suppressor cells were transferred to immunodeficient hosts having had their potential to reject male skin grafts restored with either nonimmune or specifically immune female lymphoid cells. The observed suppression of graft rejection could be accounted for, to a significant extent, by male spleen cells carried over with the transferred female cells to the assay recipients. Though an active host-derived suppressor mechanisms was not found, transferred spleen and lymph-node cells obtained from females given a prior i.v. infusion of male spleen cells were poor at restoring the capacity to reject male skin grafts to immunodeficient female recipients, whereas equal numbers of lymphoid cells from untreated females were much better. Thus, i.v. infusion of male spleen cells appeared to deplete the peripheral lymphoid tissue of the recipients of responsivity to H-Y antigen.

Induction of allograft tolerance to the H-Y antigen in adult C57BL/6 mice: Differential effects on delayed-type hypersensitivity and cytolytic T-lymphocyte activity

This study describes the induction of allograft tolerance to the “male-specific,” minor histocompatibility antigen, H-Y, in adult C57BL/6 female mice, and the effects of this tolerance induction on two immune parameters associated with graft rejection: delayed-type hypersensitivity (DTH) and cytolytic T-lymphocytes (CTL). B6 females tolerized to H-Y, by a single iv injection of C57BL/6 male lymphocytes, exhibited prolonged or permanent survival of B6 male tail skin grafts. Graft-induced DTH against H-Y antigen was reduced or abrogated in tolerized females. Delayed onset of graft rejection in partially tolerant females correlated with delayed onset of DTH, and eventual rejection of grafts was accompanied by an increase in H-Y-specific DTH. In contrast, H-Y-specific CTL activity was not consistent with graft status. These data demonstrate a correlation between H-Y-specific DTH and rejection of male skin grafts by B6 female mice and are most consistent with a major effector role for DTH in chronic graft rejection.

Prolonged minor allograft survival in intravenously primed mice--a test of the veto hypothesis.

Experiments were performed to test the hypothesis that veto cells are responsible for the prolonged survival of minor allografts of skin that is observed in recipients primed intravenously with spleen cells from mice syngeneic with the skin donors. This prolonged survival was observed for each of several minor histocompatibility (H) antigens and is antigen-specific. Gamma radiation (3300 rads) abolished the ability of male spleen cells infused i.v. to delay the rejection of male skin grafts (H-Y antigen) on female recipients. However, depletion of Thy-1+ cells from the i.v. infusion failed to abolish the ability to prolong male skin graft survival. Furthermore, the prolonged survival accorded to B6 (H-2b) male skin grafts on CB6F1 (H-2b/H-2d) female recipients given i.v. infusions of B6 male spleen cells extended to BALB/c (H-2d) male skin grafts as well, indicating a lack of MHC restriction. Thus, prolongation of minor allograft survival by i.v. infusion of minor H antigen-bearing spleen cells appears not to depend on veto T cells that others have found to be responsible for the suppression of CTL generation (2, 3, 5).

Immunogenetic control of the response of female mice to male tissue grafts.

Inbred strains of mice which carry recombinant H-2 genomes have been utilized to locate the site o f H-2 control of rejection of male liver tissue grafts by females of the same strain. When the K end of the H 2 complex carries the H 2 b allele, the strongest immunological response is evoked in female animals. However, there is a clear participation of the D end of the H 2 complex in immune response to these grafts. The background genome also plays a significant role in graft rejection in some strains. The data presented lead to the hypothesis that control over rejection of these grafts is a complex interaction of multiple genetic factors. The immunological phenomenon of rejection of male skin grafts by female mice of the same inbred strain is well documented (Gasser and Silvers 1972). This reaction is believed to result from immunological reactivity against the H-Y antigen of the male. The H 2 complex, or a gene closely linked to that complex, exerts a major control on the female's ability to reject male skin (Gasser and Silvers 1971, Bailey and Hoste 1971) and capacity to generate cytotoxic killer T lymphocytes against the Y antigen of male cells (von Boehmer et al. 1978). For example, animals carrying the H-2 b haplotype acutely reject male grafts while animals carrying the H 2 a haplotype do not. H 2 b animals are also strong generators of anti-H-Y cytotoxic T lymphocytes. However, attempts to locate the female-vs-male skin-graft response to a specific region of the H-2 complex have produced conflicting results (Bailey 1971). Female B10.A (2R) and B10.A (4R) mice, which are recombinants of the K end of H 2 ~ and the D end of H 2 b, react in the same manner as H-2 a mice while recombinants between the K end of H-2 b and the D end of H-2 a react in a comparable manner to H-2 b females in skin-graft rejection. These data suggest that the response to H-Y is located at or closely linked to the K end of the H-2 complex (Bailey 1971, Stimpfling and Reichert 1971). However, females of the HTG strain give an H-2b-like skin-graft response even though they carry the K region of the H2 d haplotype and the D region of the H 2 b haplotype. It may be concluded from these data that more than one locus is controlling the immune response of the female mice to grafts of male skin. In fact, female mice of the same H-2 type sometimes show significantly different degrees of response to male skin grafts.

Acceleration by BCG and PS-K of the rejection of male skin grafts by female mice

BCG, protein-bound polysaccharide Kureha (PS-K) and levamisole which have been used in tumor immunotherapy were studied for the effect on the rejection of male skin grafts by female mice. The graft rejection was significantly accelerated by one s.c. injection of BCG (5×105 microorganisms/mouse) into recipients on the day of transplantation. PS-K injected 250 mg/kg s.c. or i.p. once every other day from the day of transplantation significantly stimulated the graft rejection. Oral administration of 1000 mg/kg PS-K by the same schedule was also effective. Levamisole 20 mg/kg injected s.c. once on the day of transplantation was without any effect.From these results it is concluded that PS-K has an immunostimulant action similar to that of BCG. This property may be important to the antineoplastic activity of PS-K.

Genetic influences other thanH-2 on the rejection of male skin grafts by female mice

Genetic influences other thanH-2 on the rejection of male skin grafts by female mice

Effects of BCG, levamisole and PS-K on the rejection of male skin grafts by female mice

Rejection of male skin grafts by BALB/c female mice was accelerated by one s.c. injection of BCG (5 X 10(5) microorganisms/mouse) into recipients on the day of transplantation. Levamisole 20 mg/kg injected similarly was without any effect. Protein-bound polysaccharide Kureha (PS-K) injected 250 mg/kg s.c. or i.p. once every other day from the day of transplantation stimulated graft rejection. The s.c. route was more effective than the i.p. route. These results show that, in sex-linked graft rejection in mice, PS-K has an immunostimulant action similar to that of BCG. This property may be important to the antineoplastic activity of PS-K.

173 - Effects of BCG, levamisole and PS-K on the rejection of male skin grafts by female mice

Rejection of male skin grafts by BALB/c female mice was accelerated by one s.c. injection of BCG (5×105 micro-organisms/mouse) into recipients on the day of transplantation. Levamisole 20 mg/kg injected similarly was without any effect. Protein-bound polysaccharide Kureha (PS-K) injected 250 mg/kg s.c. or i.p. once every other day from the day of transplantation stimulated graft rejection. The s.c. route was more effective than the i.p. route.

Rejection of Male Skin Grafts by Splenectomized Female Mice

Female mice of the C3H strain normally do not reject skin grafts from males of the same strain; however, 40 percent of splenectomized C3H female mice completely rejected C3H male skin grafts applied 2 weeks later. All splenectomized females showed at least transitory signs of graft rejection.

Continued Expression of H-Y Antigen on Male Lymphoid Cells resident in Female (Chimaeric) Mice

REJECTION of male skin grafts by female mice of the same inbred strain is due to male-specific (H-Y) antigen1,2 (review3). As the only functions so far definitely traced to the Y chromosome are concerned with sex determination, a question arises as to whether the expression of H-Y antigen on male cells is secondary to development of the male phenotype, or whether a gene (or genes) on the Y chromosome specifies H-Y antigen (either directly or under regulation of an autosomal locus) independently of other sex-related characteristics. The fact that H-Y antigen is found on all male tissues that have been tested, rather than being restricted to sex-related tissues3,4, is perhaps an indication that it is not directly concerned with the attributes of male sexuality. Its appearance on male but not on female cells might instead be a fortuitous consequence of the lack of crossing over between the X and Y chromosomes; in this case, any change in cell surface antigenicity brought about by mutation of genes on the Y chromosome would automatically be transmitted only to males.

The Antigenic Specificity of Spermatozoa

Summary Experiments were undertaken to determine whether histocompatibility antigens were detectable on spermatozoa and whether it might be possible to differentiate spermatozoa bearing X and Y chromosomes by means of the fluorescent antibody technique. C57BL/6 female mice were immunized with skin grafts and lymphoid cells from C57BL/6 males in an attempt to produce antibody specific for Y-determined antigen(s). Despite accelerated second-set rejection of male skin grafts, it was not possible to detect antibody to Y-determined antigen in female C57BL/6 mice immunized with male tissue. It was possible to demonstrate the presence of H-2 antigens on the cell membranes of lymphoid cells but not spermatozoa by means of the fluorescent antibody technique. Using sera from both male and female C57BL/6 mice which had been immunized with sperm or testis, it was possible to demonstrate by both direct and indirect fluorescent staining techniques antibody specific for the acrosome of mouse, rat and guinea pig sperm. It is suggested that acrosomal antigen may be a cell-specific antigen of spermatozoa.