A Aitouche

A Salam

A.S Rao

Berke

H Sun

J.J Fung

L.A Valdivia

Nagata

T.E Starzl

V Subbotin

Yamagami

English

PubMed

Crossref

The role of Fas/FasL apoptotic pathway in the development of chronic rejection

Subbotin, V

Sun, H

Aitouche, A

Salam, A

Valdivia, LA

Fung, JJ

Starzl, TE

Rao, AS

Name not available

D-Scholarship@Pitt

ELSEVIER The Role of Fas/FasL Apoptotic Pathway in the Development of Chronic Rejection V. Subbotin, H. Sun, A Aitouche, A Salam, LA Valdivia, J.J. Fung, T.E. Starzl, AS. Rao FAS (CD95). a member of the tumor necrosis factor-receptor family is universallv expressed on various tissues of the body. I On the contrary. its ligand (Fas L) has a more restricted pattern of expression being found pre-dominantly on activated T cells and on discrete cells in the eye and in the testis.2 It has been recently shown that the interaction between Fas and FasL plays an important role in inducing apoptotic cell death.-' Furthermore. interactions of these molecules have also been shown to mediate tissue destruction witnessed during acute cellular rejection (ACR) of organ allografts. 4 This latter finding has prompted many to evolve novel therapeutic strategies aimed at interrupting Fas/FasL binding to mitigate or abrogate AC R. However. the role of Fas system in the pathogenesis of chronic rejection (CR) is as yet undetermined. To address this issue, FasL-deficient mice were used as donor and/or recipients of aortic allografts: reported herein is the out-come of this study. MATERIALS AND METHODS Animals Inbred male C3H/HEJ (H_2k), C3H/HEJ FasU ld (FasL -), C57Bl/6 (H_2b ; B6), and BALB/C (H_2d ) mice were purchased from Jackson Laboratory (Bar Harbor, Me) and housed in a pathogen-free facility for use at 10 to 12 weeks of age. Experimental Design The aorta (AO) was transplanted according to a method described previously;5 the recipients did not receive any treatment during the postoperative follow-up. Depending on the donor-recipient com-bination, the animals were divided into four groups (Table 1). In Vitro Analysis At approximately 40 days after transplantation. the recipient spleen, serum. and aortic grafts were harvested for in vitro analysis. Using a method described elsewhere.' anti donor cellular and humoral responses were determined by MLR and microcytotoxicity assays. respectively. Additionally, the morphology of the trans-planted AO was also evaluated using routme hematoxylin and eosin staining and immunostaining for alpha-smooth muscle actin (a-smA). elastic fibers and collagen (Verhoeff-van-Gieson's). © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 31, 1397-1398 (1999) Table 1. Experimental Groups and the Observed Outcome in Recipient Aortic Grafts Strain Groups Combinations n B6 ..... B6 5 C3H ..... C3H 5 B6 -+ C3H 5 C3H -+ B6 5 III C3H FasL -+ B6 5 IV B6 -+ C3H FasL 5 'Determmed by MLR assay. fDetermmed by mlcrocytotoxiclty. Intimal Antidonor ReactIVIty Proliferation Cellular' Humoralf +++ +++ +++ +++ +++ +++ +++ +++ +-r+ -/+ + +++ All analyses were performed at 40 days post-transplantation. RESULTS AND DISCUSSION When transplanted across syngeneic barriers. the morphol-ogy of the AD harvested at 40 days after transplantation remained unchanged being very similar to that to native AD (Table 1). As anticipated, these syngeneic recipients did not exhibit any donor-specific cellular or humoral responses (Table 1). On the contrary, grafts obtained from wild-type allogeneic recipients (Table 1: group II), had profound intimal thickening which was largely due to proliferation and/or accumulation of a-smA + cdls. Associated with this histological aberration was heightened antidonor prolifera-tive response and the presence of increased titers of circu-lating donor-specific alloantibodies (Table 1). Analogous observations were also made in 86 recipients of C3H FasL -allografts (Table I; group III). On the contrary, the majority of the 86 allografts har-vested from C3H FasL - recipients at 40 days after trans-plantation had remarkable preservation of morphology (Table 1; group IV). This was associated with markedly reduced donor-specific proliferation of enriched T cells. whereas the antidonor humoral responses remained un-changed (Table 1). Taken together. these observations From the Section of Cellular Transplantation, Thomas E. Starzl Transplantation Institute and the Departments of Pathology and Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Address reprint requests to Abdul S. Rao, MD, Thomas E. Starzl Transplantation Institute, E1545 Biomedical Science Tower, 200 Lothrop St, Pittsburgh, PA 15213. 0041-1345/99/$-see front matter PII S0041-1345(98)02042-9 1397 --~ .. ~ --K~----1398 suggest that the presence of functionally competent T cells which are capable of initiating a cellular immune response is required to induce changes in an allograft which eventu-ally leads to the development of CR. Furthermore, the presence of high titers of alloantibodies in group IV recip-ients with remarkable preservation of allograft morphology is an intriguing observation. However, it could be argued that while cellular immune responses play an important role in initiating changes characteristic of CR, alloantibodies are primarily involved in the perpetuation of this lesion. SUBBOTIN, SUN, AITOUCHE IT AL REFERENCES 1. Nagata S, Suda T: Immunol Today 16:39, 1995 2. Subbotin V, Sun H, Aitouche A: Transplantation, 1998 (submitted) 3. Yamagami S, Kawashima H, Tsuru T, et al: Transplantation 64:1107, 1997 4. Berke G: Cell 81:9, 1995 5. Sun H, Valdivia LA, Subbotin V, et al: Microsurgery, 1998 (in press) • 

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The role of Fas/FasL apoptotic pathway in the development of chronic rejection

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