Demetris, AJ

Fu, F

Fung, JJ

Qian, S

Starzl, TE

Sun, H

PubMed

D-Scholarship@Pitt

i = ----------q Liver Graft Induced Donor Specific Unresponsiveness Without Class I and/or Class II Antigen Differences S. Qian, H. Sun, AJ. Demetris, F. Fu, T.E. Starzl, and J.J. Fung L IVER allografting induces specific systemic unre-sponsiveness to subsequent other donor tissues in pigs. l rats,2 and mice.3..Although the mechanism remains unclear, soluble donor crass I major histocompatibility complex (MHC) antigens and/or anti-donor class II al-loantibodies have been proposed as critical components of the induced unresponsiveness.2.4.5 If those explanations are correct, a liver graft should not be able to protect extrahepatic tissues if one or both of these potential mechanisms are inoperative. In the present study, the induction of unresponsiveness by liver allografts was ob-served in mouse strain combinations where there was class I MHC mismatching only (B lOAKM--+B lOBR, absence of anti-donor class II antibodies), class II MHC mismatching only EAqe~AqiI absence of class I alloantigens), and only minor histocompatibility complex (mHC) mismatch-ing (B lOBR ~ C3H, absence of both class I and class II alloantigens). The results offered a perspective about the role of factors other than soluble class I antigens and class II antibodies in explaining the mechanisms of liver al-lograft-induced tolerance. MATERIALS AND METHODS Animals All mice used in this study were purchased from Jackson Labo-ratory (Bar Harbor, Me) and then kept at the University of Pittsburgh Animal Facility until use. Ten to 12-week-old male mice were used as donors and recipients in liver, heart, and skin transplantation. Liver, Heart, and Skin Transplantations Orthotopic liver transplantation was performed by Qian's tech-nique as previously described.6 Heterotopic heart transplantation was performed in the abdomen using the method of Corry7 immediately after liver grafting. Heart graft function was assessed daily by palpation. Rejection was defined as the total cessation of palpable pulsation, confirmed by autopsy and histologic examina-tion. Skin grafting was completed by placing full thickness tail skin grafts (8 mm x 8 mm) on the dorsal ftank of the recipient. Grafts were held in place by a gauze dressing and a tape for at least 7 days. The grafts were assessed daily thereafter. Rejection was defined as complete graft destruction. Donor skins were trans-planted on to the liver recipients more than 100 days following acceptance of the hepatic grafts. No immunosuppressive therapy was used in this study. RESULTS Almost all donor skin and heart grafts in liver grafted recipients survived more than 100 days (Table I), even when no class I MHC alloantigen mismatching (ATH to A TL) and no class II MHC alloantigen mismatching (B lOAKM to B WBR) were present, or both class I and class II alloantigens were mismatched (B lOBR to C3H). The heart grafts in B IOAKM to B lOBR combinations were spontaneously accepted long term even without prior liver grafting (data not shown). The results in this study suggest that the donor-specific systemic unresponsiveness induced by liver allografting may not be due to soluble MHC class I antigens and/or MHC class II antibodies, which have long been proposed as the components responsible for liver graft-induced unresponsiveness. From the Departments of Surgery (S.O., H.S., F.F., T.E.S .• J.J.F.) and Pathology (A.J.D.), University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania. Address reprint requests to Shiguang Oian, MD. University of Pittsburgh, Transplantation Research Laboratory, E1540 Biomed-ical Science Tower, Pittsburgh, PA 15260. © 1993 by Appleton & Lange 0041-13451931$3.001 +0 Table 1. Survival of Donor Grafts In Liver Grafted Recipient Uver Donor Recipient None C3H C57BU10 C3H None B10BR B10AKM B10BR None ATl ATH ATl None C3H B10BR C3H Disparity 1,II,mHC II mHC Skin 15,18,19 39,>100.>100.>100 13.13,23.23.23 Donor Graft SWvIvai (d) >100, >100. >100. >100. >100 14.16,19,19,19 56: >100, >100 20.22.22.23 >100. >100. >100, 100 Heart 7, 7, 7, 7, 7 >100, >100 9.11,19,22.23 >100, >100 13, 13, 13. 13 >100. >100. >100 Abbravtations: I. major histocompatibility complex class I: II. major histocompatibility comptex class II . • Animal died with living skin graft. 362 Transplantation Proceedings, Vol 25, No 1 (February), 1993: pp 362-363 -,.-LIVER ALLOGRAFT IN MICE DISCUSSION The immunosuppressive properties of liver grafting have b~en intriguing for decades. When the liver is transplanted wIth other organs, the additional donor original grafts are rejected less vigorously than expected.8 .9 The mechanisms remain obscure, although they have been actively investi-gated. Soluble donor class I antigens released by liver graft lO have been considered as main components contrib-uting to tolerance induction. As recently reported in- a 'rat model,4 continuous infu-sion of donor soluble class I antigen induced a marginal prolongation of heart graft survival (from 8.1 ± 0.7 to 10.0 ± 1.5 days), which was amplified by adding the monoclo-nal anti-class I antibody (15.6 ± 3.0 days). However, the results of the present study in the mouse model show that liver transplantation is able to induce systemic tolerance. in the combinations where the donor and recipient share the same MHC class I antigens. Therefore, it, is unlikely that allogeneic MHC class I antigen or antibodies exist. since the donor and recipient are syngeneic for these molecules. Anti-donor class II antibodies have been proposed as another mechanism of the immunosuppressive effects of liver grafting. In the rat model. anti--allo-class II MHC antibody titers reached their high levels and were main-tained for several months after liver grafting:5 However. marginal enhancement was achieved by transferring liver grafted recipient rat serum IgG from which antibodies to class I antigens had been absorbed. Therefore the class II antibodies present in liver grafted rat serum were consid-ered to be the factor responsible for enhancement. II •12 363 However, in our mouse model, liver graft-induced unre-sponsiveness existed in a system where there was no class II disparity, and therefore alloantibodies to class II are unlikely to be present. In B lOBR to C3H combination donor and recipient shared the same MHC. Despite that there were no allogeneic class I antigens and anti-class II antibodies in recipient serum, the liver grafts were still able to protect both skin and heart grafts. The results of this in vivo study suggest that it is inappropriate to overempha-size the role of class I alloantigens and/or class II MC alloantibodies in explanation of liver graft-induced specific unresponsiveness. REFERENCES I. Caine RY. Sell RA. Pena JR. et al: Nature 223. 1969 2. Zimmerman FA, Butcher HS, Davis G. et al: Transplant Proc 11:571, 1979 3. Qian S. Fung JJ. Demetris AJ, et al: Transplant Proe 23:705. 1991 4. Sumimoto R, Kamada N: Transplantation 50:678. 1990 5. Kamada N. Shinomiya T: Transplantation 42:7, 1986 6. Qian S, Fung JJ, Demetris AJ. et al: Transplantation 52:562, 1991 7. Corry RJ, Winn HJ, Russell PS: Transplant Proc 5:733.1973 8. Margreiter R, et al: Transplant Proe 20:522, 1988 9. Grant D, et al: Lancet 335:181, 1990 10. Davies HFFS. Pollard SG. Caine RY: Transplantation 47:524, 1989 11. Kamada N, Sumimoto R, Bagurizo A. et al: Immunology 68:315, 1988 12. Kamada N, Shinomiya T, Tamaki T, et aI: Transplantation 42:581, 1986 

Liver graft induced donor specific unresponsiveness without class I and/or class II antigen differences.

Name not available

Liver graft induced donor specific unresponsiveness without Class I and/or Class II antigen differences

http://d-scholarship.pitt.edu/4923/1/31735062113265.pdf

Liver graft induced donor specific unresponsiveness without class I and/or class II antigen differences.

Abstract

Similar works

Full text

Available Versions

D-Scholarship@Pitt

Name not available

Name not available