Mechanisms of Rejection and Prolongation of Vascularized Organ Allografts

Tilney, Nicholas L.; Kupiec‐Weglinski, Jerzy W.; Heidecke, Claus Dieter; Lear, P. A.; Strom, Terry B.

doi:10.1111/j.1600-065x.1984.tb00722.x

Cited by 60 publications

(26 citation statements)

References 102 publications

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“…We analyzed whether the events of chronic rejection were localized primarily in the engrafted donor organ or whether they were also manifest in host lymphoid tissues. Unlike the situation in acute rejection where there is much extraallograft activity (22), we found that every cytokine, regardless of donor organ source, was expressed below the internal control of f3-actin in spleens except IL-2R, which was up-regulated to 1.5 times at 52 weeks in the spleens of the allograft recipients (data not shown). …”

Section: Resultsmentioning

confidence: 85%

“…Lymphocytes and macrophages may persist in both organ allografts and isografts with and without clinical evidence of dysfunction. In this in vivo study, we used an established and reproducible chronic rejection model in rat kidneys that develops progres- sive changes similar to those in human renal allografts (22,23) to analyze sequential cytokine expression.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1.

Nadeau

Azuma

Tilney

1995

Proc. Natl. Acad. Sci. U.S.A.

201

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Chronic rejection, the most important cause of long-term graft failure, is thought to result from both alloantigen-dependent and -independent factors. To examine these influences, cytokine dynamics were assessed by semiquantitative competitive reverse transcriptase-PCR and by immunohistology in an established rat model of chronic rejection of renal allografts. Isograft controls develop morphologic and immunohistologic changes that are similar to renal allograft changes, although quantitatively less intense and at a delayed speed; these are thought to occur secondary to antigen-independent events. Sequential cytokine expression was determined throughout the process. During an early reversible allograft rejection episode, both T-cell associated [interleukin (IL) 2, IL-2 receptor, IL-4, and interferon y] and macrophage (IL-la, tumor necrosis factor a, and IL-6) products were up-regulated despite transient immunosuppression. RANTES (regulated upon activation, normal T-cell expressed and secreted) peaked at 2 weeks; intercellular adhesion molecule (ICAM-1) was maximally expressed at 6 weeks. Macrophage products such as monocyte chemoattractant protein (MCP-1) increased dramatically (to 10 times), presaging intense peak macrophage infiltration at 16 weeks. In contrast, in isografts, ICAM-1 peaked at 24 weeks. MCP-1 was maximally expressed at 52 weeks, commensurate with a progressive increase in infiltrating macrophages. Cytokine expression in the spleen of allograft and isograft recipients was insignificant. We conclude that chronic rejection of kidney allografts in rats is predominantly a local macrophage-dependent event with intense up-regulation of macrophage products such as MCP-1, IL-6, and inducible nitric oxide synthase. The cytokine expression in isografts emphasizes the contribution of antigen-independent events. The dynamics of RANTES expression between early and late phases of chronic rejection suggest a key role in mediating the events of the chronic process.

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Section: Resultsmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1.

Nadeau

Azuma

Tilney

1995

Proc. Natl. Acad. Sci. U.S.A.

201

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“…Cells bearing the phenotype ofactivated T lymphocytes are of particular interest in transplantation immunobiology because they represent a functionally diverse ensemble engaged in the allograft response (3,4). Unlike their resting counterparts, activated T cells bear insulin receptors (20), transferrin receptors (21), and IL-2 receptors (5-8).…”

Section: Discussionmentioning

confidence: 99%

“…Although the pivotal role of sensitized T lymphocytes in graft rejection has been long appreciated, the complex interplay among functionally defined cell phenotypes, distinctive surface protein markers expressed by these cells, and cytokines elaborated by them are not fully defined (3,4). Helper-T-cell (Th)-derived interleukin 2 (IL-2) is the main cytotrophic factor for immunocompetent T lymphocytes (5).…”

mentioning

confidence: 99%

Therapy with monoclonal antibody to interleukin 2 receptor spares suppressor T cells and prevents or reverses acute allograft rejection in rats.

Kupiec‐Weglinski¹,

Diamantstein²,

Tilney³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

107

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The mouse hybridoma ART 18 monoclonal antibody (mAb), which binds to the rat interleukin 2 (IL-2)receptor, was studied for its effect on heterotopic cardiac allograft survival m Two 'histoincompatible inbred rat strain combinations. Treatment with ART 18 mAb for 10 days after transplantation proloagediallograft survival in a dose-dependent fashion up to about 3 weeks (acute rejection normally occurs within 8 days). ART 18 mAb therapy started at 5 days after transplantation (the--time of major rejection activity) abrogated acute rejection dnd extended the survival to about 18 days. The dense cellular infiltrate noted histologically in acute rejection had virtually disappeared after ART 18 mAb treatment. Thus, IL-2 receptortargeted therapy can be successfully used to prevent and/or treat acute rejection. When spleen cells from antibody-treated recipients bearing well-functioning allografts were adoptively transferred to normal untreated rats that received cardiac; allografts 24 hr later, the survival of donor-specific, but not third-party, test cardiac allografts was prolonged significantly; this supports the idea that ART 18 mAb induced "sparing" of suppressor T lymphocytes. Combining infusion of ART 18 mAb with exogenous IL-2-rich conditioned medium produced the same effect as if the mAb alone had been administered, suggesting that an excess of IL-2 does not prevent binding of ART 18 mAb to IL-2 receptorbearing cells in vivo. These results support the important role of the IL-2 receptor,-bearing cells in the mechanism of allograft rejection; they may represent an important target for immunosuppression in clinical organ transplantation.Treatment of allograft rejection remains the major problem in clinical organ transplantation (1,2). Antirejection therapy has included high doses of steroids and polyclonal anti-lymphocyte globulins; more recently, cyclosporine and monoclonal anti-T-cell antibodies have been used. Unfortunately, these powerful immunosuppressive modalities have been only relatively successful and may produce serious complications, particularly life-threatening infections. Thus, although results of clinical transplantation have improved progressively, new strategies are still needed to obtain the elusive goal of donor-specific immunosuppression and "tolerance" by the host toward a foreign graft.Although the pivotal role of sensitized T lymphocytes in graft rejection has been long appreciated, the complex interplay among functionally defined cell phenotypes, distinctive surface protein markers expressed by these cells, and cytokines elaborated by them are not fully defined (3, 4).Helper-T-cell (Th)-derived interleukin 2 (IL-2) is the main cytotrophic factor for immunocompetent T lymphocytes (5). (9). The mouse ART 18 monoclonal antibody (ART 18 mAb), which reacts primarily with rat lymphoblasts, defines the rat IL-2 receptor (10-12). This antibody inhibits adsorption of IL-2 by IL-2 receptor-positive cells, thereby blocking IL-2-dependent T-lymphocyte proliferation. We have utilized ART 18 mA...

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“…Several models have therefore been advanced to study the functional characteristics of infiltrating graft cells and their role in rejection. In vitro functional assays of enzymatically isolated lymphocytes from rejected organs have demonstrated allospecificity [17]. The sponge-allograft model has been employed to study the kinetics of graft infiltration [18,19].…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of infiltrating T lymphocytes in human hepatic allografts

et al. 1986

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We have employed recently developed techniques in T-cell culturing to study the nature and function of infiltrating hepatic allograft T cells. Using the rationale that intragraft T cells are activated during cell mediated damage to the allograft, we were able to show that these cells would propagate and remain functionally active in the presence of the T-cell growth factor, IL-2. In several instances, phenotypic analysis of cells grown in this manner was very similar to that found within the graft. Both proliferative and cytotoxic responses could be detected from the cultured cell lines. The majority of the proliferative responses were donor-directed and immunogenetic analysis could define donor-directed HLA reactivity, to either class I or class II antigens, or both. Monoclonal anti-HLA antibodies inhibition profiles verified the apparent HLA reactivity. In a smaller percentage of cases, only IL-2 responsiveness could be detected, and no HLA reactivity could be determined. Cytotoxicity could be detected against both class I and class II antigens, however, those cells which demonstrated a greater magnitude of donor-directed cytotoxicity appeared to be directed against class I antigens. A significant correlation between donor-directed proliferation of biopsy cultured lymphocytes and cellular rejection was found. This model appears to be useful in delineating functions of the intragraft T-cell population during rejection.

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Mechanisms of Rejection and Prolongation of Vascularized Organ Allografts

Cited by 60 publications

References 102 publications

Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1.

Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1.

Therapy with monoclonal antibody to interleukin 2 receptor spares suppressor T cells and prevents or reverses acute allograft rejection in rats.

Functional characterization of infiltrating T lymphocytes in human hepatic allografts

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