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Analysis of chronic rejection and obliterative arteriopathy: Possible contributions of donor antigen-presenting cells and lymphatic disruption

Demetris, AJ and Murase, N and Ye, Q and Galvao, FHF and Richert, C and Saad, R and Pham, S and Duquesnoy, RJ and Zeevi, A and Fling, JJ and Starzl, TE (1997) Analysis of chronic rejection and obliterative arteriopathy: Possible contributions of donor antigen-presenting cells and lymphatic disruption. American Journal of Pathology, 150 (2). 563 - 578. ISSN 0002-9440

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Abstract

Sequential analysis of changes that lead to chronic rejection was undertaken in an animal model of chronic rejection and obliterative arteriopathy. Brown Norway rats are pretreated with a Lewis bone marrow infusion or a Lewis orthotopic liver allograft and a short course of immunosuppression. They are challenged 100 days later with a Lewis heterotopic heart graft without immunosuppression. The heart grafts in both groups undergo a transient acute rejection, but all rats are operationally tolerant; the heart grafts are accepted and remain beating for more than 100 days. Early arterial remodeling, marked by arterial bromodeoxyuridine incorporation, occurred in both groups between 5 and 30 days during the transient acute rejection. It coincided with the presence of interstitial (but not arterial intimal) inflammation and lymphatic disruption and resulted in mild intimal thickening. Significant arterial narrowing occurred only in the bone-marrow-pretreated rats between 60 and 100 days. It was associated with T lymphocyte and macrophage inflammation of the heart graft that accumulated in the endocardium and arterial intima and adventitia near draining lymphatics. There also was loss of passenger leukocytes from the heart graft, up-regulation of cytokine mRNA and major histocompatibility class II on the endothelium, and focal disruption of lymphatics. In contrast, long-surviving heart grafts from the Lewis orthotopic liver allograft pretreated group are near normal and freedom from chronic rejection in this group was associated with persistence of donor major histocompatibility class-II-positive hematolymphoid cells, including OX62 + donor dendritic cells. This study offers insights into two different aspects of chronic rejection: 1) possible mechanisms underlying the persistent immunological injury and 2) the association between immunological injury and the development of obliterative arteriopathy. Based on the findings, it is not unreasonable to raise the testable hypothesis that direct presentation of alloantigen by donor antigen-presenting cells is required for long-term, chronic-rejection-free allograft acceptance. In addition, chronic intermittent lymphatic disruption is implicated as a possible mechanism for the association between chronic interstitial allograft inflammation and the development of obliterative arteriopathy.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Demetris, AJ
Murase, N
Ye, Q
Galvao, FHF
Richert, C
Saad, R
Pham, S
Duquesnoy, RJ
Zeevi, A
Fling, JJ
Starzl, TEtes11@pitt.eduTES11
Centers: Other Centers, Institutes, or Units > Thomas E. Starzl Transplantation Institute
Date: 21 February 1997
Date Type: Publication
Journal or Publication Title: American Journal of Pathology
Volume: 150
Number: 2
Page Range: 563 - 578
Institution: University of Pittsburgh
Refereed: Yes
ISSN: 0002-9440
Other ID: uls-drl:31735062127034, Starzl CV No. 1981
Date Deposited: 08 Apr 2010 17:33
Last Modified: 13 Oct 2017 22:58
URI: http://d-scholarship.pitt.edu/id/eprint/5367

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