A.J Demetris

J Reyes

K Abu-Elmagd

Monchik

Murase

N Murase

Q Ye

R.G Lee

Starzl

T.E Starzl

PubMed

Murase, N

Ye, Q

Lee, RG

Demetris, AJ

Abu-Elmagd, K

Reyes, J

Starzl, TE

Name not available

Immunomodulation of intestinal transplant with allograft irradiation and simultaneous donor bone marrow infusion

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D-Scholarship@Pitt

ELSEVIER Immunomodulation of Intestinal Transplant With Allograft Irradiation and Simultaneous Donor Bone Marrow Infusion N. Murase, Q. Ye, R.G. Lee, A.J. Demetris, K. Abu-Elmagd, J. Reyes, and T.E. Starzl PASSENGER LEUKOCYTES. normal constituents of all organs. migrate after transplantation and produce persistent multilineage microchimerism. which modulates the recipient immune system and is suggested to have an important role in inducing graft acceptance after transplan-tation.1.2 Leukocytes in the intestine have been shown to have inferior tolerogenic qualities compared with bone marrow (BM) cells; in addition. leukocytes have a lineage profile predisposed to graft-versus-host disease (GYHD).3 We hypothesized that intestinal allograft alteration with ex-vivo irradiation will eliminate mature lymphoid elements from the graft without degrading the function of the epithelial components. Furthermore. we hypothesized that the replacement of irradiated graft passenger leukocytes with simultaneous donor BM infusion will improve the result of intestinal transplantation (SITx). This possibility was examined using the rat model of SITx. METHODS Inbred male Lewis (LEW. RT11) and Brown Norway (BN, RTln) rats were purchased from Harlan Sprague DaWley. Inc .• (indianap-olis, IN) and used as donors and recipients. respectively. Small intestinal grafts were obtained from LEW donors and ex vivo irradiated from 137CS source before orthotopic SITx. Donor BM was obtained by flushing the tibias and femurs. and a total of 2.5 x 108 cells was intravenously infused into recipients on the dav of SITx. FK 506 (l mg/kg/d) was intramuscularly given to recipi~nts on days 0-13. 20. and 21, Percentages of donor Ieukocvtes were determined sequentially in recipient blood by flow cvtom~try using monoclonal antibodies specific for major histocompatibility com-plex (MHC) class I antigens on LEW and BN. RESULTS All recipients of unmodified intestinal grafts died of G VHD despite simultaneous donor BM infusion in some cases. Median survivals were 63 and 51 davs with and without simultaneous donor BM infusion. respectively (n = 5 for each). Graft irradiation (10 Gy) effectively prevented GVHD. and median animal sUlVival was prolonged to 92.5 days without BM infusion. Further prolongation was achieved by adjunct BM. All animals in this group sUlVived for more than 100 days (n = 6). Percentages of donor cells © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 31, 565-566 (1999) in the peripheral blood correlated with animal sUlVival. Donor phenotype cells remained at low levels (less than 2f7c) after transplantation of lO-Gy irradiated grafts. whereas they were consistently high in GVHD recipients of unaltered grafts. No major histopathological abnormalities caused by irradiation. such as irradiation vasculopathy, were found in to Gy irradiated grafts 100 to 200 days after SITx. DISCUSSION SUlVival of graft passenger leukocytes was proved when donor leukocytes (microchimerism) were found in recipi-ents whose allografts had been functioning for decades. 1,2 The implication was that donor hematopoietic progenitor cells. including prulipotent stem cells. present in the trans-planted organ had migrated and sUlVived in the recipient. Before this finding, transplantation had been defined largely in terms of a unidirectional immune reaction. and this one-way paradigm had failed to elucidate numerous enigmatic obselVations. including the surprising clinical success of organ transplantation. The discovery of micro-chimerism has provided new insights into the immunologi-cal events following organ transplantation and prompted the development of new strategies. In the field of SITx. GVHD has been a major concern since Monchik and Russell showed the development of GVHD in semiallogenic SITx using the parent-to-offspring Fl hybrid model.4 In fact. previous studies of intestinal graft modification have attempted to reduce the risk of GVHD using irradiation. antilymphocyte serum. or surgical manip-ulation. Based on the recent discovery of microchimerism and the current understanding of the dual immune reaction after organ transplantation (host-versus-graft [HVG] and graft-versus-host [GVH]). we have examined methods of intestinal graft conditioning and recipient immune modu-lation. This study shows the beneficial effects of graft From the Thomas E. Starzl Transplantation Institute, Depart-ments of Surgery and Pathology, University of Pittsburgh, Pitts-burgh, Pennsylvania. Address reprint requests to Dr Murase, Thomas E. Starzl Transplantation Institute. Department of Surgery, University of Pittsburgh, Transplantation Institute. E1540 Biomedical Science Tower, Pittsburgh. PA 15261. 0041-1345/99/$-see front matter PI! S0041-1345(98)01556-5 565 566 irradiation and adjuncti\'e donor 8M infusion on graft survival. Preliminary results suggest that the superiority of this strategy is associated with the rapid replacement of graft lymphoid tissues with recipient leukoCYtes of the same lineages. Further study is currently underwa\' to improve SITx from its present state of excessive mortality and morbidity. MURASE. YEo LEE ET AL REFERENCES 1. Starzl TE. acmetri~ AJ. Murasc N. ct al: Lancet 339:1579. 1992 2. Starzl TE. Zinkcrnagcl R: N Engl J Mea 339:24. 1998 3. Murase N. Starzl TE. Tanabe M . .:1 al: Transplantation 60: 158. 1995 4. Monchik. Russell: Surgcrv 70:fJ93. 1971 

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Immunomodulation of intestinal transplant with allograft irradiation and simultaneous donor bone marrow infusion

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