Intestinal allografts delay rejection and prolong survival of combined donor-specific and third party solid organ transplants

Intestinal Allografts Delay Rejection and Prolong Survival of Combined Donor-Specific and Third Party Solid Organ Transplants T. Koshiba, B. Van Damme, P. Ji, Y. Lu, Y. Yan, H. Sefrioui, O. Rutgeerts, L. Overbergh, K. Tanaka, C. Mathieu, M. Waer, and J. Pirenne

I

NTESTINAL transplantation (Itx) causes an extremely vigorous rejection. How this immune response affects rejection of other distant simultaneously transplanted organs is not known. The intestinal graft contains a large amount of lymphoid tissues,1 causes bacterial translocation at the time of reperfusion injury and acute rejection,2 and strongly expresses MHC antigens on the enterocyte.3 These unique aspects may promote rejection not only of intestinal graft itself but also of other distant simultaneously transplanted organs. Thus, we searched to determine whether Itx aggravates rejection of another organ in a model of combined intestinal and heart transplantation. MATERIALS AND METHODS Male RA (RT1p) rats (100 to 150 g) were used as donors of heart grafts. Male RA, BN (RT1n) or PVG (RT1C) rats (150 to 200 g) were used as donors of intestinal grafts. Male PVG rats(RT1c) (200 to 250 g) were used as recipients. Ether anesthesia was used.

Operative Procedure The entire small intestine was harvested with the portal vein and supra renal aortic conduit as previously described.4,5 Large infrarenal vessels in the recipient were exposed and end-to-side anastomoses were done with the portal vein and the aortic conduit of the graft. The proximal end of the graft was closed and the distal end was anastomosed with the native intestine in an end-to-side fashion. RA intestinal graft transplanted in PVG showed histological rejection at postoperative day (POD) 8 but not at POD 3. In group 6 (Table 1), RA intestinal graft was completely removed including the mesenteric lymph nodes at POD 3 before histological

rejection begins. Clinical rejection was defined as the appearance of a palpable mass through the abdominal wall. After entire small intestinal transplantation, all branches of mesenteric vessels were ligated and cut to remove the intestine, whereas vascularized mesenteric lymph nodes were left in the abdomen (Fig 1). A heart graft was transplanted in the right cervix of the recipient in an isolated fashion or combined with above mentioned Itx or MLN tx. The aorta and the pulmonary artery of the graft were sutured with the common carotid artery and the external jugular vein of the recipient, respectively. In case of double heart transplantations, heart grafts were transplanted in the cervix and the abdomen.6 Rejection was defined as cessation of heart beating. According to operative modalities (the presence or the absence of Itx, donor strain of intestinal graft), seven different groups were tested. To test an antigen dose-dependent phenomenon, two hearts (identical donor) were transplanted simultaneously (group 2). To check the effect of surgical trauma, syngeneic Itx was combined with alloHtx (group 3). To investigate the effect of intestinal graft cell migration to the recipient, the intestinal graft was completely removed 3 days after combined Htx/donor-specific Itx (group 6) or combined Htx/ donor-specific MLN tx was performed (group 7). Differences were tested using unpaired t test.

Abdominal Transplant Surgery, Laboratory for Experimental Transplantation, and Pathological Department, Catholic University of Leuven (KUL), Leuven, Belgium and Immunology and Transplantation Department, Kyoto University, Kyoto, Japan. Address reprint requests to Prof Jacques Pirenne, Catholic University of Leuven (KUL), Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium.

Table 1. Experimental Transplantation Groups

Group Group Group Group Group Group

1 2 3 4 5 6

Group 7

Modality

Number

Heart Donor

Intestine or MLN Donor

Recipient

Isolated Htx Double Htx Combined Htx/syngeneic Itx Combined Htx/donor-specific Itx Combined Htx/third-party Itx Combined Htx/donor-specific Itx but intestine removed at POD 3 Combined Htx/MLN tx

5 3 5 5 5 3

RA RA RA RA RA RA

— — PVG RA BN RA

PVG PVG PVG PVG PVG PVG

3

RA

RA

PVG

0041-1345/01/$–see front matter PII S0041-1345(00)02589-6

© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

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Transplantation Proceedings, 33, 1550–1552 (2001)

INTESTINAL ALLOGRAFTS

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Fig 1. Mesenteric lymph node transplantation (MLN tx). After entire small intestinal transplantation, intestine was simply removed and only vascularized mesenteric lymphnodes remain in the abdomen.

RESULTS

In the isolated Htx group (group 1), the heart survived 8.2 ⫾ 0.8 days. When RA Htx were simultaneously performed with donor-specific RA Itx, heart graft survival was prolonged to 19 ⫾ 4.3 days. (group 4; P ⬍ .05 vs group 1). RA Htx survival was only slightly prolonged when syngeneic

PVG Itx was simultaneously done (group 3; 10.2 ⫾ 0.8 day; P ⬍ .05 vs group 1). Third-party BN Itx prolonged survival of RA Htx, but this effect was not as strong as with RA Itx (group 5; 14 ⫾ 6.3 days; NS vs group 1) although RA and BN intestinal grafts showed the evidence of clinical rejection in the same tempo (13 ⫾ 0.8 days vs 14 ⫾ 3 days; NS).

Fig 2. Donor-specific RA Itx prolonged survivals of RA Htx most prominently; whereas, PVG Itx or BN Itx only slightly prolonged survivals of RA Htx.

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KOSHIBA, VAN DAMME, JI ET AL Table 2. Survivals of RA Heart Graft in PVG

Group Group Group Group Group Group

1 2 3 4 5 6

Group 7

Modality

Individual Survival (d)

Mean (SD) (d)

P

Isolated Htx Double Htx Combined Htx/syngeneic Itx Combined Htx/donor-specific Itx Combined Htx/third party Itx Combined Htx/donor-specific Itx but intestine removed at POD 3 Combined Htx/MLN tx

7.8.8.9.9 7.8.9 9.10.10.11.11 15.16.17.22.25 10.10.12.13.25 11.12.14

8.2 (0.8) 8 (1.0) 10.2 (0.8) 19 (4.3) 14 (6.3) 12.3 (1.5)

NS vs group 1 ⬍.05 vs group 1,2 ⬍.05 vs group 1,2,6,7 NS vs group 1,2,6,7 ⬍.05 vs group 1,4

When 2 RA heart grafts were transplanted, RA Htx survival was not different (group 2; 8.0 ⫾ 1.0 days; P ⬎ .05 vs group 1). When RA intestinal graft was removed 3 days after combined Htx/donor-specific Itx (group 6) or donor-specific RA MLN tx was simultaneously done (group 7), RA Htx survival was slightly prolonged to 12.3 ⫾ 1.5 days and 11.0 ⫾ 2.6 days, respectively (P ⬍ .05, and NS vs group 1, respectively) but these effects were not as strong as in group 4 (P ⬍ .05 vs group 4, respectively). SUMMARY

First, we show that ongoing Itx rejection protects simultaneous Htx. Second, donor-specific protection is stronger than third party protection although both donor-specific and third-party intestinal grafts are rejected in the same tempo. Third, this protection is not observed when two heart grafts (identical donor) are transplanted, suggesting that this protection is provided only by rejecting Itx. Fourth, Htx survival is only slightly prolonged due to the effect of surgical trauma when combined with syngeneic (non-rejecting) Itx. Fifth, transient Itx (graft removal at POD 3) or MLN tx alone prolonged Htx survivals only to an extent similar to syngeneic (non-rejecting) Itx, implying that intes-

8.12.13

11 (2.6)

NS vs group 1 ⬍.05 vs group 4

tinal passenger leukocytes or the mesenteric lymph nodes are not sufficient for significant prolongation of Htx survival.

CONCLUSION

Although Itx produces a vigorous rejection respose, it does not necessarily aggravate rejection in distant simultaneously transplanted organs. Unlike we hypothesized, ongoing rejection of Itx may delay rejection in distant simultaneously transplanted organ.

REFERENCES 1. Iwaki Y, Starzl TE, Yagihashi A, et al: Lancet 337:818, 1991 2. Grant D, Hurlbut D, Zhong R, et al: Transplantation 52:221, 1991 3. Schmid T, Oberhuber G, Korozsi G, et al: Transplant Int 3:73, 1990 4. Monchik GJ, Russel PS: Surgery 70:693, 1971 5. Zhong R, Grant D: Microsurgery 12:268, 1991 6. Ono K, Lindsey ES: J Thorac Cardiovasc Surg 57:225, 1969