Genetic aspects of the blood transfusion effect.

The genetic requirements for the induction of the blood transfusion effect have been investigated in a genetically well-defined model. The survival of fully vascularized, heterotopic murine cardiac allografts was measured after a single preoperative transfusion of blood from mice selected to share MHC and/or minor histocompatibility (miH) antigens with the organ donor. The effect of a transfusion from a donor unrelated to the heart donor (third-party transfusion) on allograft survival was also determined. Five strain combinations were used for these experiments. The results obtained illustrate a number of important aspects of the blood transfusion effect in this model: (1) Donor-specific blood transfusion, where MHC and miH were shared by the blood donor and the organ donor, always induced prolonged graft survival. (2) The sharing of the whole MHC (H-2) by the blood donor and organ donor was found to be sufficient to prolong allograft survival in the five fully allogeneic strain combinations tested. (3) The sharing of miH antigens only was not sufficient to induce prolonged cardiac allograft survival. Special cases were identified showing that several factors could interact to potentiate the action of miH antigens in the induction of the blood transfusion effect. (4) Transfusion with blood from a third-party donor was effective in some strain combinations. In one recipient, blood from several third-party strains of mice, sharing neither MHC nor miH antigens with the organ donor, induced prolonged graft survival. We suggest that the mechanism by which third-party blood has a beneficial effect on graft survival is through crossreaction(s) between the blood donor and the organ donor. The results obtained in this study fit very well with one model for the cellular mechanism by which the transfusion effect may be mediated. This may be the means by which blood from randomly selected donors has a beneficial effect on graft survival in clinical transplantation.

Inability of dendritic cells to prevent the blood transfusion effect in a mouse cardiac allograft model.

The beneficial effect of blood transfusions before clinical renal transplantation is well established, but this can result in sensitization of some potential first graft recipients. Dendritic cells (DC), present in human blood, are potent stimulators of immune responses in vitro and in vivo, and in different systems they can overcome immune unresponsiveness. We therefore investigated whether DC could prevent the transfusion effect in a murine cardiac allograft model. C57BL/10 (C57) hearts were normally rejected by untreated DBA/2 recipients with a median survival time (MST) of 17 days. Long-term survival (MST greater than 100 days) was induced when the recipients were transfused with C57 blood 14 days before transplantation (d-14). Similar survival times were obtained when up to 1.5 x 10(5) splenic DC were added to the transfused blood. This number of DC or as few as 10(3), in "unsorted" preparations that were 70-85% pure, similarly enhanced when transfused alone at d-14. This enhancement was probably due to the contaminating cells rather than the DC since 10(3) lymphocytes prolonged survival, but an equivalent dose of "sorted" DC (ca. 93% pure, most contaminating cells being removed by sorting on an Ortho Cytofluorograf) did not. Transfusion of unsorted preparations containing 1.5 x 10(5) DC at d-3 led to accelerated graft rejection (MST 4 days). This sensitization was most likely due to the DC because equivalent numbers of lymphocytes were ineffective. Nevertheless, if a blood transfusion was given at d-14 followed by a normally sensitizing dose of DC at d-3, graft survival was still prolonged. Thus in no case were DC able to prevent the blood transfusion effect in this strain combination. Furthermore, DC of donor origin given to DBA/2 recipients with long-surviving C57 hearts, produced by prior blood transfusion, did not trigger rejection of the hearts.

The role of H-2 and non-H-2 antigens and genes in the rejection of murine cardiac allografts.

Genes of the major histocompatibility complex (MHC) in the mouse (H-2 complex) have been shown to be an important factor in determining the immune responsiveness of various strains of mice to isolated antigens (e.g., lysozyme). The role of MHC genes in controlling the responsiveness of mice to multiple alloantigens is less well-defined, and although non-MHC genes have been shown to be important in determining responsiveness in some systems (e.g., haptens), they have not been demonstrated as yet to influence the rejection of vascularized organ allografts. In this study, the responsiveness of mice to vascularized cardiac allografts transplanted across well-defined major (H-2) and minor (non-H-2) histocompatibility barriers was investigated using congenic mice in 32 different donor/recipient combinations. The results show that both H-2 and non H-2 gene products can act as target alloantigens for rejection. At the responder level, they may interact to effect responsiveness of a recipient strain to multiple alloantigens. In no case in this study has any one gene or group of genes been found to confer universal high or low responder status.