Anti-Interleukin 2 Receptor Monoclonal Antibody in the Treatment of Ongoing Acute Rejection Episodes of Human Kidney Graft-a Pilot Study

Cantarovich, Diego; Hourmant, Maryvonne; Giral, M.; Denis, M; Hirn, M.; Jacques, Yannick; Soulillou, Jean‐Paul

doi:10.1097/00007890-198903000-00011

Cited by 36 publications

(3 citation statements)

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“…None of the antibodies is used clinically without other immunosuppressive drugs and none of the antibodies can be recommended for treatment of acute rejeetion. Cantarovich et al [26][27][28] treated 10 acute rejection episodes in kidney transplant patients with the p55 antibody 33B3.1, They suggest that "once lL-2dependent clones are expanded in the rejected graft, interference with IL-2/IL-2-R signals does not block the effector mechanisms sustaining acute rejection". That the effector mechanisms of T cells do not depend on IL-2 is demonstrable in every chromium release assay.…”

Section: Discussionmentioning

confidence: 99%

“…Thus IL-2-R blocking with 33B3.1 is not effective enough or is bypassed by other cytokines. Additionally, Cantarovich et al demonstrate [26][27][28] that 33B3,1 has no relevant antibodydependent cellular cytotoxicity (ADCC) in vivo during acute rejection. The rat IgG2a antibody 33B3.I does not appear to be superior to the mouse IgGI antibodies BT563 and anti-Tac-M in terms of any sort of cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

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Interleukin‐4 Bypass of the Immunosuppressive Effect Mediated by Interleukin‐2 Receptor Antibodies

1993

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Numerous studies have demonstrated that the generation of alloreactive effector cells depends on cytokines. Conversely, there is evidence that cytokine metabolism is altered at the clonal level in tolerant chimaeras. This has led to preclinical and clinical studies using antibodies that antagonize interleukin-2 (IL-2), with the hope of achieving immunosuppression and inducing tolerance. Monoclonal antibodies against the alpha-chain (p55) of the human IL-2 receptor are being applied to prevent transplant rejection and graft-versus-host disease in several clinical trials. The antibodies that have been applied clinically so far antagonize the binding of IL-2 to the IL-2 receptor alpha-chain which is part of the high affinity IL-2 receptor, but they do not deplete the receptor-bearing cells. Our study investigates the immunosuppressive effect of monoclonal antibodies against the alpha-chain (p55) and beta-chain (p75). In mixed lymphocyte cultures the p55 antibody causes a reduction in T-cell proliferation to about 50%. The generation of cytotoxic T cells is reduced more effectively (up to 80%). By additional blocking of the IL-2 receptor beta-chain we achieved an additional but still incomplete immunosuppressive effect. Moreover we show that IL-2 receptor-blocked alloreactive T cells escape suppression by using IL-4 as an alternative stimulating signal. To prevent T lymphocytes benefiting from this alternative and thwarting the immunosuppressive effect, cytotoxic IL-2 receptor antibodies that deplete the high affinity receptor-bearing cells are needed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interleukin‐4 Bypass of the Immunosuppressive Effect Mediated by Interleukin‐2 Receptor Antibodies

1993

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“…Intragraft macrophage and endothelial expression of tissue factor are associated with extensive local fibrin deposition, whereas CD25, tissue factor expression, and widespread fibrin deposition are not present in biopsies from patients with cyclosporin toxicity or normal renal function posttransplantation (3,4). A pivotal role for these IL-2R + mononuclear cells in mediating kidney rejection is demonstrated by the successful treatment or, in some cases, prevention of allograft rejection in clinical (5) and experimental (6, 7) studies using CD25 mAbs.…”

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confidence: 99%

Tumor necrosis factor production during human renal allograft rejection is associated with depression of plasma protein C and free protein S levels and decreased intragraft thrombomodulin expression.

Tsuchida¹,

Salem²,

Thomson³

et al. 1992

The Journal of Experimental Medicine

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SummaryFibrin deposition is a common accompaniment of renal allograft rejection, indicating disruption of the normal physiologic balance between procoagulant and anticoagulant pathways. In vitro, tumor necrosis factor (TNF) induces endothelial expression of the procoagulant, tissue factor, and downregulation of thrombomodulin, a key component of the thrombomodulin/protein C (PC)/protein S (PS) pathway, which normally maintains an anticoagulant state by inactivating thrombin, preventing further thrombin formation by degrading factors Va and VIIIa, and decreasing plasminogen activator inhibitor activity. Raised levels of TNF were recently demonstrated within the blood of patients during episodes of renal allograft injection, and may be an early and discriminatory marker of rejection. This led us to investigate prospectively whether monitoring of serum TNF levels was of value dinically, and was associated with effects on circulating PC and PS levels, or alterations in intragraft thrombomodulin expression. Plasma samples (n = 454) were collected three times/week from all patients (n = 25) undergoing renal transplantation during a 9-month consecutive period, and assayed by ELISA and functional assays for TNF, PC, and free PS (FPS). Portions of renal biopsies, taken to evaluate episodes of acute deterioration of renal function, were evaluated by immunoperoxidase labding for the presence and distribution of TNF, thrombomodulin, PC, PS, thrombin, fibrin, and factors V and VIII. Comparison of 78 plasma samples collected during 26 episodes of biopsy-proven acute cellular rejection with samples collected during periods of stable renal function (n = 349) showed that TNF levels rose significantly (390 +_ 242 pg/ml, p < 0.01) above background levels 3 days before rising serum creatinine concentrations, and peaked (2,426 _+ 978 pg/ml) on the day of clinical rejection. PC-antigen (Ag) concentrations also decreased 3 days before rejection (68 _+ 13%, p < 0.05), and were maximally depressed (49% _+ 16%, p < 0.001) on the day of rejection. FPS levels were normal until the day before rejection (63% +_ 8%, p < 0.01) and, like PC, were maximally depressed (43 + 10%) at rejection. Plasma TNF levels were significantly and inversely correlated with PC-Ag (p < 0.001) and FPS (p < 0.005) levels during rejection, regardless of whether such rejection episodes were steroid responsive or required OKT3 monoclonal antibody therapy. TNF, PC, and FPS levels were normal during episodes of cydosporine toxicity and viral infection. Immunoperoxidase studies showed that rejection was associated with a intrarenal production of TNF, decreased microvascular labeling for thrombomodulin, and widespread endothelial and interstitial deposition of PC, PS, thrombin, fibrin, and factors V and VIII. These findings suggest that TNF is an important mediator of renal allografr rejection, causing depression of the intragraft thrombomodulin/PC/PS pathway and thereby contributing to intragraft fibrin deposition. Moreover, these results indicate that monitoring of circ...

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Immunosuppression

Drews

1990

Immunopharmacology

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Anti-Interleukin 2 Receptor Monoclonal Antibody in the Treatment of Ongoing Acute Rejection Episodes of Human Kidney Graft-a Pilot Study

Cited by 36 publications

References 0 publications

Interleukin‐4 Bypass of the Immunosuppressive Effect Mediated by Interleukin‐2 Receptor Antibodies

Interleukin‐4 Bypass of the Immunosuppressive Effect Mediated by Interleukin‐2 Receptor Antibodies

Tumor necrosis factor production during human renal allograft rejection is associated with depression of plasma protein C and free protein S levels and decreased intragraft thrombomodulin expression.

Immunosuppression

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