The Effect of Anti-Interleukin-2 Receptor Monoclonal Antibody on Allograft Rejection

Kirkman, Robert L.; Barrett, Leslie V.; Gaulton, Glen N.; Kelley, Vicki Rubin; Koltun, Walter A.; Schöen, Frederick J.; Ythier, Armelle; Strom, Terry B.

doi:10.1097/00007890-198512000-00029

Cited by 51 publications

(19 citation statements)

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“…The isolation and preliminary characterization of monoclonal antibodies to human (23), murine (9,24), and rat (10-12) IL-2 receptors have been reported. One of these antibodies, ART 18 IgG1 mAb was raised in mice primed with phorbol 12-myristate 13-acetate-treated rat T lymphoblasts (10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

“…Administration of rat anti-mouse M7/20, a mAb that binds to the murine IL-2 receptor, has been shown to prolong, often indefinitely, mouse cardiac allograft survival (9). In the present studies, we have attempted to combat acute rejection of heterotopic cardiac allografts in otherwise unmodified rat recipients, focusing therapy selectively at the IL-2 receptor-bearing target cells.…”

Section: Discussionmentioning

confidence: 99%

“…Because all proliferating T cells express IL-2 receptors (5-8), IL-2 receptor-targeted therapy delivered in the peritransplantation period should create a selective immune defect in the graft recipient. However, there is little information available on the use of anti-IL-2 receptor monoclonal antibodies in a setting of transplantation, with the exception of a study using a mouse allograft model (9).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Blockade of IL-2 signaling has long been recognized as a route to achieving immune suppression and prolonging graft survival (Kirkman et al 1985;Reed et al 1989;Masri 2003). Prior to the discovery of therapeutic antibodies, IL-2 signaling was prevented by corticosteroids, cyclosporine (via calcineurin inhibition), and rapamycin (through the mTOR pathway) (Hardinger et al 2004;Ponticelli 2005;Geissler et al 2008).…”

Section: Allograft Transplantationmentioning

confidence: 99%

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Wilson

Arkin

2010

Current Topics in Microbiology and Immunology

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“…Our success in deploying anti-IL-2 receptor ␣ chain monoclonal antibodies in preclinical models of autoimmunity 21 and preclinical [22][23][24] and clinical [25][26][27][28] transplantation led to the development of two FDA-approved antihuman IL-2 receptor monoclonal antibodies that are now used with considerable safety and efficacy in clinical practice. Moreover, the development and eventual FDA approval of a chimeric IL-2 toxin-related molecule was spurred, 20,29 -34 in part, by the unfortunate discovery that my mother-in-law was afflicted with an IL-2 receptorpositive T cell malignancy.…”

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confidence: 99%