Celli, S

Fung, JJ

Madariaga, J

Pan, F

Park, IY

Rao, AS

Starzl, TE

Sun, H

Valdivia, LA

Wakizaka, Y

English

PubMed

D-Scholarship@Pitt

Use of MHC Class I or II "Knock Out" Mice to Delineate the Role of These Molecules in Acceptance/Rejection of Xenografts H. Sun, Y. Wakizaka, A.S. Rao, F. Pan, J. Madariaga, loY. Park, S. Celli, J.J. Fung, T.E. Starzl, and L.A. Valdivia I T has previously been reported that pretreatment of human islets with anti-MHC class I antibodies leads to their prolonged survival when subsequently transplanted into naive mice, suggesting that, as in allotransplantation, these molecules also playa role in the recognition and the initiation of effector responses to xenoantigens,l However, this protracted survival of cellular, unlike primary vascular-ized organ transplants, can also be ascribed partially to their inherent resistance to antibody-mediated injury; a feature largely attributed to the neovasculature. which is essentially of recipient origin. Of the vascularized organs, liver but not heart xenografts are an exception: they are relatively resis-tant to humoral rejection. thereby allowing for the devel-opment of cell-mediated responses." This peculiar observa-tion provides a unique opportunity to study the role of donor MHC class I and class II cell surface molecules in the acceptance or rejection of primary vascularized xenografts. To this end. we used MHC class I and class II "knock out" mice as donors of organs (liver and heart), which were transplanted into naive rat recipients. Furthermore, the influence of MHC disparity on xenograft survival in the reciprocal (rat to mouse) combination was also investi-gated. MATERIALS AND METHODS Rat to Mouse Experiments. Hearts ohtained from 2- to 3-week-old ACI (RTla) or LEW (RTl') rats were heterotopically trans-planted into adult BIO or C3H mice. Mouse 10 Rat Experiments. Hearts (heterotopic) or livers (ortho-topic) were transplanted from normal C3H (H_2k ). BIO (H_2h). B6 (H_2h ). or MHC class 1 (B6: b2m) or class II (86: CD2) deficient mice into naive 3- to 4-week-old LEW recipients. RESULTS AND DISCUSSION Rat to Mouse. C3H mice rejected LEW and ACI hearts in 5.6 ± 0.5 and 7.1 ± 0.8 days, respectively (P < .0(01). whereas 810 mice rejected these grafts in 8.5 ± 0.7 and 7.7 ± D.7 days. respectively (P < .(03). Histopathological analysis of rejected cardiac xenografts revealed mononu-clear cell intiltration with widespread thrombosis. Mouse to Rat. Hearts obtained from 810. C3H. or 86 mice. when transplanted into LEW rats. were rejected in 732 <3 days. Similar survival was also noted when hearts from MHC class I or class II knock out mice were transplanted into naive LEW recipients. The predominant effector mech-anism appeared to be humoral. because histopathological analysis revealed widespread thrombosis and interstitial hemorrhage with mild cellular infiltration. Unlike hearts. mouse livers obtained from naive animals enjoyed pro-longed survival (6 to 10 days) when transplanted into LEW rats. However, similar to our observations in hearts, the lack of expression of class I or class II antigens in the trans-planted liver had no appreciable effect on prolonging its survival following transplantation. Interestingly. no discern-ible difference was noted in the titers of rat antimouse cytotoxic antibodies in the serum of LEW recipients of hearts or livers from b2m. CD2, or normal 86 mice. Taken together, these observations suggest that the ex-pression of donor MHC class I and class II cell-surface antigens may have an insignificant role in determining the tempo of rejection of xenografts transplanted from mouse to rat. It is therefore tempting to speculate that in this model. species-specific epitopes may playa more dominant role than MHC antigens in eliciting humoral or cellular responses. REFERENCES I. Faustman D. Coc C: Science 252:1700.1991 2. Valdivia LA. Fung JJ. Demetris AJ. et al: Transplant Proc 23:3269. 1991 From the Pittsburgh Transplantation Institute and the Depart-ments of Surgery (H.S .. Y.w .• A.S.R.. F.P., J.M., I.Y.P., S.C., J.J.F., T.E.S .• L.A.V.) and Pathology (A.S.R), University of Pitts-burgh Medical Center. Pittsburgh, Pennsylvania. Aided by project grant no. DK29961 from the National Insti-tutes of Health, Bethesda. MD. Address reprint requests to LUIS A. Valdivia. MD. PhD. Pitts-burgh Transplantation Institute. E1546 Biomedical Science Tower, 200 Lothrop Street. Pittsburgh. PA 15261. © 1996 by Appleton & Lange 0041-1345/96/$3.00/ + 0 Transplantation Proceedmgs. Vol 28. No 2 (Apnl). 1996: p 732 

Use of MHC class I or II 'knock out' mice to delineate the role of these molecules in acceptance/rejection of xenografts

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Use of MHC class I or II 'knock out' mice to delineate the role of these molecules in acceptance/rejection of xenografts

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