M. Tsugita

Donor species complement after liver xenotransplantation : the mechanism of protection from hyperacute rejection

Hamster hearts transplanted into stable rat recipients of hamster livers (OLT rats) were hyperacutely rejected after transfer with unaltered rat antihamster hyperimmune serum (HS). This was followed by immediate liver xenograft rejection in 4 of 5 rats. In contrast, simple heat inactivation of the rat HS resulted in prolonged survival of hamster hearts to 25 days without deterioration effect in the liver xenografts. This effect was species-specific because third-party mouse heart grafts in OLT rats were hyperacutely rejected in minutes if either active or heat inactivated antimouse HS was given. In cytotoxicity experiments, the complement in OLT serum produced weak lysis of hamster lymphocytes, while efficiently doing so with mouse cell targets. Because normal hamster serum caused no lysis at all of hamster target cells, the residual low-grade lysis of OLT serum was possibly being mediated by extrahepatic sources of rat C. In conclusion, the homology of C and target cells represents a mechanism of protection that the liver confers to other organs, and that is most easily seen in xenografts but may be allospecifically operational with allografts as well within the limits of MHC restriction.

Functional cooperation of xenoproteins after hamster-to-rat liver transplantation: With particular reference to hamster C3 and secretory component for rat IgA

Abstract: Long‐term survival after hamster‐to‐rat liver xenotransplantation has provided the opportunity to study the posttransplantation source of major serum proteins and the functional consequences of several different receptor‐ligand interactions, where one or the other is a xenogeneic protein. We report here that serum albumin, α‐1‐antitrypsin, complement component 3, and other acute phase reactants switch from recipient to donor origin during the first week after transplantation while serum immunoglobulins remain largely that of recipient. Despite the disparate source of complement (hamster) and immunoglobulins (rat), these two proteins were able to cooperate effectively to produce lysis of sheep red blood cells. Moreover, rat IgA was successfully processed by hamster hepatocytes and biliary epithelial cells, being present in the bile of successful liver xenograft recipients within one day after transplantation. The ability of these liver xenograft recipients to survive long‐term in conventional and viral‐free animal facilities without grossly obvious morbidity or unusual susceptibility to stress, suggests that xenogeneic proteins are able to successfully interact with several different physiologic I systems in the hamster‐to‐rat combination.

Tacrolimus pretreatment attenuates preexisting xenospecific immunity and abrogates hyperacute rejection in a presensitized hamster to rat liver transplant model.

In the hamster to rat liver transplant model, we determined the efficacy of tacrolimus in attenuating natural xenospecific humoral immunity and in abrogating the hyperacute liver rejection that is produced by presensitizing the Lewis rat recipient. Hamster livers, transplanted orthotopically into naive rats (controls), were rejected with animal death after 6.4.+/- 0.5 (SD) days. The infusion on (day -6) of 1.5 x 10(7) hamster hepatocytes, or of 1.5 x 10(8) nonparenchymal cells (NPC), resulted in hyperacute rejection and death in < or = 1.9 days. However, when the rats were pretreated with 1 mg/kg/day tacrolimus from days -6 to -1, survival of non-presensitized animals was prolonged to 25 +/- 20 days and that of recipients presensitized with hamster hepatocytes to 36 +/- l6 days or with NPC to 32 +/- 1.7 days. The tacrolimus pretreatment significantly reduced the hamster-specific complement-dependent cytotoxic antibodies response directed to liver NPC but not to lymph node cell targets. These observations suggest that the prolongation of survival by appropriately timed treatment with this T cell directed drug model is caused by the inhibition of humoral as well as cellular xenograft rejection.

Donor-specific transfusion in the nude rat prolongs survival of subsequently transplanted hamster cardiac xenografts☆

Xenograft tumors have indefinite survival when transplanted into athymic nude rats or mice. However, nude rats reject vascularized hamster cardiac xenografts in tempo (3 to 4 days) similar to that of immunocompetent rats.1–3 This “slow-motion” hyperacute rejection witnessed in the nude rat is thought to be mediated by a T cell-independent, but antibodyand complement-dependent mechanism(s).1 In this study, we investigated whether prior exposure of nude rat recipients to hamster xenoantigens in the form of donor-specific transfusion (DST), would modulate the humoral response thus allowing for prolonged survival of subsequently transplanted cardiac xenografts.