Origin of lymph node-derived lymphocytes in human hepatic allografts

Hepatic allograft-derived lymph nodes were examined in the post-transplant period on order to determine the origin of lymphocytes and structural elements of the lymph node. Histologic assessment and immunohistochemical studies verified that T-cell infiltration of donor lymph nodes by recipient-derived lymphocytes occurred early in the post-transplant period. These T cells bore T-cell activation markers, e.g. TAC receptor and HLA-DR antigens. In addition, functional analysis demonstrated alloreactive T cells in secondary proliferation assays. The pattern of alloreactivity in these assays was dependent upon the phenotypic make-up (and therefore origin) of the lymphocytes within the lymph node. A gradual shift in predominance of donor-derived lymphocytes to recipient-derived lymphocytes occurred, but even late in the post-transplant course the stromal elements and a residium of lymphocytes within the lymph nodes continued to bear donor HLA antigens. The possible role of these 'passenger' lymphocytes in allograft immunity is discussed

Recognition of major histocompatibility complex antigens on cultured human biliary epithelial cells by alloreactive lymphocytes

We have developed an in vitro system to study the interactions between biliary epithelium and lymphocytes using cultured human biliary epithelial cells. No class II antigens were detected by immunoperoxidase staining of the normal biliary epithelial cells, but alloactivated lymphocyte culture supernatants were able to induce class II expression. The activity of the supernatants was blocked with an anti‐γ‐interferon monoclonal antibody. In addition, recombinant human γ‐interferon alone induced the expression of class II antigens and increased the intensity of class I staining of cultured biliary epithelial cells. Biliary epithelial cell‐induced proliferation of alloreactive T lymphocytes demonstrated that the major histocompatibility complex molecules carry functional lymphocyteactivating determinants. The recognition of major histocompatibility complex determinants was confirmed by monoclonal antibody‐blocking studies and by stimulation of an alloreactive T‐cell clone. However, the biliary epithelial cells were much less potent stimulators than arterial endothelial cells tested in the same assay system. (HEPATOLOGY 1991;13:239–246). Copyright © 1991 American Association for the Study of Liver Disease

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

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

Weaning of immunosuppression in long - Term liver transplant recipients

Seventy-two long-surviving liver transplant recipients were evaluated prospectively, including a baseline allograft biopsy for weaning off of immunosuppression. Thirteen were removed from candidacy because of chronic rejection (n=4), hepatitis (n=2), patient anxiety (n=5), or lack of cooperation by the local physician (n=2). The other 59, aged 12-68 years, had stepwise drug weaning with weekly or biweekly monitoring of liver function tests. Their original diagnoses were PBC (n=9), HCC (n=l), Wilson’s disease (n=4), hepatitides (n=15), Laennec’s cirrhosis (n=l), biliary atresia (n=16), cystic fibrosis (n=l), hemochromatosis (n=l), hepatic trauma (n=l), alpha-l-antitrypsin deficiency (n=9), and secondary biliary cirrhosis (n=l). Most of the patients had complications of long-term immunosuppression, of which the most significant were renal dysfunction (n=8), squamous cell carcinoma (n=2) or verruca vulgaris of skin (n=9), osteoporosis and/or arthritis (n=12), obesity (n=3), hypertension (n=ll), and opportunistic infections (n=2). When azathioprine was a third drug, it was stopped first. Otherwise, weaning began with prednisone, using the results of corticotropin stimulation testing as a guide. If adrenal insufficiency was diagnosed, patients reduced to <5 mg/day prednisone were considered off of steroids. The baseline agents (azathioprine, cyclospo-rine, or FK506) were then gradually reduced in monthly decrements. Complete weaning was accomplished in 16 patients (27.1%) with 3-19 months drug-free follow-up, is progressing in 28 (47.4%), and failed in 15 (25.4%) without graft losses or demonstrable loss of graft function from the rejections. This and our previous experience with self-weaned and other patients off of immunosuppression indicate that a significant percentage of appropriately selected long-surviving liver recipients can unknowingly achieve drug-free graft acceptance. Such attempts should not be contemplated until 5-10 years posttransplantation and then only with careful case selection, close monitoring, and prompt reinstitution of immunosuppression when necessary. © 1995 by Williams & Wilkins