Characterization of Forssman and Other Antigen/Antibody Systems in Vascularized Mouse Heart to Rat Xenotransplantation

Abstract

In the present study, the nature of hyperacute xenograft rejection was closely studied in a vascularized mouse-to-rat transplantation model. Antibodies against mouse heart, erythrocytes and lymphocytes and against the Forssman antigen were raised in the rat. Upon heterotopic heart transplantation the respective antisera were intravenously (i.v.) injected. Passive transfer of antiheart, antierythrocyte or antilymphocyte serum resulted in hyperacute rejection of the transplanted mouse heart. Subfractionation of the antiheart serum showed that the capacity to induce hyperacute rejection was carried by the immunoglobulin (Ig)G fraction. When antierythrocyte serum adsorbed with mouse erythrocytes was administered the cardiac grafts remained beating. To the contrary, antilymphocyte serum adsorbed with erythrocytes still had the capacity to induce hyperacute rejection. None of the rats that had previously been challenged with the Forssman antigen rejected their grafts hyperacutely. Subsequent investigations by electron microscopy revealed that the Forssman antigen is expressed on dendritic cells (DC) adjacent to the vessels, but not on the vascular endothelium, thus explaining the inability of the anti-Forssman serum to induce hyperacute rejection. Taken together, we have demonstrated the existence of several xenoantigens that can be targets for antibodymediated rejection, suggesting that more than one relevant xenoantigen exists also in more distantly related combinations, such as the pig-to-human combination.

Antibody responses to xenogenic antigens—a study in the mouse‐to‐rat system

“…Some are probably also present on mouse blood cells because there are high titres of haemagglutinating and lymphocytotoxic antibodies present in the rat sera after rejection, as our previous study confirmed (14). Moreover, passive transfer of antierythrocyte or antilymphocyte sera shortly after transplantation induces hyperacute rejection (9). Thus, the mouse heart is believed to share antigens with mouse erythrocytes and with mouse lymphocytes.…”

“…Some of the antigens relevant for the rejection process of a mouse‐to‐rat heart transplant are present on both mouse MNC and erythrocytes. Thus, hyperimmune sera from rats immunised with either cell type will induce hyperacute rejection when administered in conjunction with mouse heart transplantation (9). Nevertheless, more antigens of importance may exist because blood transfusions and extensive immunosuppression cannot induce humoral unresponsiveness in the mouse‐to‐rat model (10).…”

Intragraft cytokine mRNA expression in rejecting and non‐rejecting vascularized xenografts

“…Adding CyA to the DSG treatment diminished the binding of antibodies to the grafts. By using haemagglutination assay and flow cytometry against mononuclear antigens as a measure of antibody response capable of inducing rejection [19], the low titres in the sera of all recipients of all six treatment groups were confirmed. Because of the DSG‐treated grafts having deposits of both IgM and IgG in the musculature on day 8 but not on day 2, the cell‐mediated rejection may also have an antibody component.…”

Pretransplant Xenogeneic Blood Transfusions Reduce the Humoral Response in a Mouse‐to‐Rat Heart Transplantation Model

“…One suggestion is that the humoral unresponsiveness in concordant xenotransplantation is mediated by mechanisms occurring in the graft endothelium [9]. Furthermore, passive transfer of sera from rats immunized by transfusions with either mouse erythrocytes or lymphocytes leads to subsequent hyperacute rejection of a transplanted mouse heart [10]. These findings implicate the presence of important xenoantigens in mouse blood cells.…”