Demetris, AJ

Fung, JJ

Qian, S

Starzl, TE

Sun, H

English

PubMed

Name not available

Transplantation unresponsiveness induced by liver allografts in mouse strains with various histocompatibility disparities

D-Scholarship@Pitt

Transplantation Unresponsiveness Induced by Liver Allografts in Mouse Strains With Various Histocompatibility Disparities S. Oian, J.J. Fung, H. Sun, A.J. Demetris, and T.E. Starzl L ONG-TERM survival of fully allogeneic liver grafts without immunosuppression and induction of donor-specific systemic unresponsiveness to subsequent extrahe-patic grafts have been documented in pigs l and rats. 2 However. the mechanisms of unresponsiveness are still poorly understood.3 Since a mouse model of orthotopic liver transplantation (OLT) has been established.4 it has become possible to more thoroughly investigate the ge-netic and immunologic basis for this unresponsiveness. In the present study. three strain combinations crossing var-ious histocompatibility barriers (all with long-term liver graft acceptance) were chosen to determine the ability of liver grafting to induce donor-specific unresponsiveness to subsequent skin grafts. MATERIALS AND METHODS Animals Inbred strains of 10- to 12-week-old male mice. C57BUIO. C3H. BIOAKM. BIOBR. and BIOD2 were purchased from the jackson Laboratory (Bar Harbor. Me) for use in these experiments. The H-2 haplotypes of strains used are shown in Table I. Surgical Procedures OLT was performed in combinations of C57BUIO to C3H. BIOAKM to BIOBR. and BIOBR to C3H using previously pub-lished techniquesK~ Full-thickness tail skin grafts were placed on the dorsum of the mice who had accepted liver grafts for more than 100 days. according to Billingham and Medawar.5 Band tapes were used to keep the grafts in place for 7 days and then removed. No immunosuppression was used in this study. The skin grafts were examined once a day for the first 2 weeks and 2 to 3 times a week thereafter. Skin grafts that failed from obvious technical complications were excluded from further analysis. Skin grafts that survived more than 100 days were biopsied for histological studies. RESULTS Despite transplantation across various histocompatibility barriers in the three groups studied. long-term (> 100 days) liver allograft survival was achieved in all animals. except for one in each group (41. 80. and 68 days. respectively). Table 1. ~O Haplotypes of Strains Used Alleles al H-2 Loci H-2 Strains HaJiOIYpe K At, A Eo E 0 C3H k k k k k k k C57BU10 b b b b b b b Bl0BR k k k k k k k Bl0AKM m k k k k k q Bl002 d d d d d d d The survival of skin grafts is shown in Table 2. Without prior liver transplantation. all allogeneic skin grafts were acutely rejected. Histologically verified donor specific unresponsiveness to allogeneic grafts was observed in all liver tolerant mice. regardless of the strain combination. Third-party skin grafts were uniformly rejected. DISCUSSION The unique properties of liver allografts have been studied for decades. As early in 1965. Garnier and colleagues discovered that allogeneic orthotopic liver grafts were able to escape irreversible rejection in the pig.7 Caine et al then demonstrated that liver grafts induced donor-specific hy-poresponsiveness to subsequent skin or kidney grafts from the same donor. One explanation for this observation involved the release of soluble MHC antigens by the grafted liver. I Ten years later. Zimmerman observed the same results in the inbred rat. 2 Since then. inbred rats have been the major source of information on liver graft tolero-genesis.s This is the first attempt at investigating tolerogenic and immunosuppressive properties of liver grafts in inbred mice. The advantages of using mice are obvious. Numer-ous genetically well-defined mouse strains and a plethora of immunologic reagents are available to study the genetics and immunology associated with the unresponsive state. Using this model. results identical to those observed in inbred strains of rats were achieved. Namely. liver grafts were able to induce donor-specific unresponsiveness to subsequent skin grafts in mouse strains with various his-toincompatibilities. Interestingly. in the BIOBR to C3H combination. which crossed only minor histocompatibility barriers. the liver grafts were able to induce unresponsiveness to subsequent skin grafts. Therefore, the induction of unresponsiveness by liver grafting is not restricted solely to the MHC system. but likely involves the minor histocompatibility complex as well. From the Department of Surgery and Pathology. University of Pittsburgh, School of Medicine. Pittsburgh. Pennsylvania. Address reprint requests to Shiguang Oian. MD. University of Pittsburgh. Transplantation Research Laboratory. El540 Biomed-ical Science Tower. Pittsburgh. PA 15260. ~ 1992 by Appleton & Lange 0041·13451921$3.001 +0 Transplantation Proceedings, Vol 24. No 4 (August), 1992: pp 1605-1606 1605 1606 alAN. FUNG. SUN ET AL Table 2. Skin Graft Survivals Uver Donor Recipient Disparity None C3H KbAbEbOb + MHC· C57BU10 C3H C57BU10 C3H None Bl0BR oq Bl0AKM Bl0BR Bl0AKM Bl0BR None C3H MHC· Bl0BR C3H B1DBR C3H 'Mlnor histocompatibility. tSl0D2 as third party. REFERENCES I. Caine RY. Pena JR. Davis DR. et al: Nature 223:472. 1969 2. Zimmerman FA. ButcherGW. Davis HIfS, et al: Transplant Proc II :571. 1979 3. Davies HIfS. Pollard SG. Caine RY: Transplant Proc 23: 2248. 1991 Skin Donor Skin Survival (d) C57BU10 15. 18. 19 C57BU10 >100. >100 Bl002t 13.13.13 Bl0AKM 13.13.23.23.23 Bl0AKM 23. >100. >100. >100 Bl002 13.13.13,13 Bl0BR 22.23 Bl0BR >100. >100 B10D2t 13.13 4. Qian S, Fung JJ, Demetris AJ, et al: Transplantation 52:562, 1991 5. Billingham RE. Medawar PB: J Exp Bioi 28:385. 1951 6. Qian S. Fung JJ, DemetJis AJ. et al: Transplant Proc 23:705, 1991 7. Gamier H. Clot JP. Bertrand M. et al: C R Acad Sci 260:5621. 1965 8. Kamada N. Davies HIfS, Roser B: Nature 292:840, 1981 

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Transplantation unresponsiveness induced by liver allografts in mouse strains with various histocompatibility disparities

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