Cyclosporin A and tolerance induction in experimental animals

Lim, Susan M. L.; White, David J.

doi:10.1007/978-94-009-0859-8_5

Cited by 3 publications

(5 citation statements)

References 42 publications

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“…This occurs, for example, in rats pretreated with CsA and donor-specific blood transfusion before allograft transplantation (6). Tolerance to allografts has usually been attributed to antigen-specific suppressor cells (5,7). However, in accordance with our findings with su-perAg, a recent study with limiting dilution analysis suggests that CsA may induce tolerance to allografts by provoking the elimination of graft-reactive T cells (38).…”

Section: Discussionsupporting

confidence: 86%

“…These effects are poorly understood and often contradictory, since in some cases a short course of CsA treatment has induced tolerance to allografts, while in other experimental models this drug has provoked autoimmune phenomena (8). Enhanced tolerance has often been attributed to the action of suppressor cells (5,7), while the paradoxical induction of autoimmune diseases has been imputed to defective thymocytic differentiation (9,10). Nevertheless, for a variety of reasons, we hypothesized that CsA could also act by affecting peripheral T cell tolerance mechanisms (i.e., peripheral deletion and anergy).…”

Section: Discussionmentioning

confidence: 99%

“…It is well accepted that the principal inhibitory action of CsA is the result of impaired lymphokine production by T cells, especially IL2 (2)(3)(4). In rats, a form of long-term nonimmunosuppressed tolerance to allografts can be induced by a short course of CsA treatment (5,6). The underlying mechanism is not well understood, but may depend on the generation of antigenspecific suppressor cells (5,7).…”

mentioning

confidence: 99%

“…In rats, a form of long-term nonimmunosuppressed tolerance to allografts can be induced by a short course of CsA treatment (5,6). The underlying mechanism is not well understood, but may depend on the generation of antigenspecific suppressor cells (5,7). Paradoxically, in some circumstances, CsA treatment can have detrimental effects, which include the induction of autoimmune diseases and syngeneic GVHD (reviewed in reference 8).…”

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confidence: 99%

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Cyclosporin A markedly enhances superantigen-induced peripheral T cell deletion and inhibits anergy induction.

Vanier

Prud’homme

1992

The Journal of Experimental Medicine

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SummaryCyclosporin A (CsA) is a well-known immunosuppressive agent that modulates immune tolerance in many ways. CsA can give rise to a state of long-term nonimmunosuppressed transplantation tolerance, but it can also aggravate autoimmune diseases, and provoke specific forms of antoimmunity. These effects, which are often paradoxical, remain largely unexplained. In this study, we investigated the effects of CsA on superantigen (superAg)-reactive peripheral T cells. The intravenous injection of either staphylococcal enterotoxin B (SEB), or Mls-1 a cells into Mls-1 b recipients, causes longterm in vitro nonresponsiveness (anergy) and partial elimination of the peripheral T call receptor (TCR) VB8+/CD4 + and -VB6+/CD4 + T cell subsets, respectively. We report that CsA markedly enhances the peripheral elimination of SEB-and Mls-la-reactive T cells such that up to 90% of the targeted CD4 +/V3 subpopulations are deleted. The degree of deletion depends on the dose and the schedule of CsA administration, and the number of superAg injections. In situations where the extent of deletion is only moderate, we find that the remaining superAgreactive T cells fail to develop anergy, unlike the T cells of control superAg-immunized mice.Higher doses of CsA are required to enhance T cell deletion (t>25 mg/kg/d, i.p.) than to impair anergy induction (>16.25 mg/kg/d, i.p.). In view of these results, it appears that the degree of tolerance in CsA/superAg-treated mice depends on the balance between these opposing effects, i.e., enhancement of peripheral elimination versus the abrogation of anergy. The possibility of enhancing or preventing immune tolerance with a drug may have important clinical implications.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cyclosporin A markedly enhances superantigen-induced peripheral T cell deletion and inhibits anergy induction.

Vanier

Prud’homme

1992

The Journal of Experimental Medicine

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“…Subcutaneous (s.c.) injections were performed once daily from day 0 to 9 and a volume of 0.2 ml of a specific suspension was injected in rats weighing 200g to reach the target dose. Cyclosporine A (CsA, Sandimmun  100 mg/ml; Novartis, Basle, Switzerland) was dissolved in Intralipid  (200 mg/ml, Pharmacia & Upjohn, Lund, Sweden) to a final concentration of 4 mg/ml and given orally for ten days [11]. A volume of 0.5 ml was given once daily to rats weighing 200 g. CsA was given immediately pre-operatively and AR-C117977 three hours before transplantation.…”

Section: Compoundsmentioning

confidence: 99%

The effect of Monocarboxylate Transporter (MCT1) inhibitor, AR-C117977 on accelerated rejection of cardiac grafts in pre-sensitised rats and concordant xenotransplantation

Paul¹,

Bundick²,

Craggs³

et al. 2018

Trends in Transplant

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Previous studies have demonstrated the immunosuppressive properties of the monocarboxylate transporter MCT1 inhibitor, AR-C117977. The objective of this study was to evaluate the possible limitations in immunosuppressive efficacy of AR-C117977 in models of hyper acute rejection of cardiac transplants in pre-sensitised rats and in concordant cardiac xenotransplantation. Methods:A primary graft was given without treatment in order to induce sensitisation. At 10 days, a second cardiac transplant was performed, and doses of the test compound were given and compared to or combined with cyclosporin (CsA). Serum samples were retrieved for flow cytometry and measurements of antibody from the presensitised recipients before and after the second transplantation.Results: Survival was significantly prolonged with AR-C117977 in combination with CsA (median 12.5 days) compared with single treatment. AR-C117977 had a better effect on antibody formation and binding to B-cells than CsA, but a similar effect on T-cells. Acute rejection could not be prevented in any of the treatment groups in the xenotransplant model. Conclusion:A short course of the MCT1 inhibitor AR-C117977, in combination with CsA, prevented accelerated acute rejection in presensitised rats, but no longterm graft survival was achieved. Rejection in xenotransplantation was not prevented.

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Immunosuppression in transplantation

Russ¹

1992

Medical Journal of Australia

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Cyclosporin A and tolerance induction in experimental animals

Cited by 3 publications

References 42 publications

Cyclosporin A markedly enhances superantigen-induced peripheral T cell deletion and inhibits anergy induction.

Cyclosporin A markedly enhances superantigen-induced peripheral T cell deletion and inhibits anergy induction.

The effect of Monocarboxylate Transporter (MCT1) inhibitor, AR-C117977 on accelerated rejection of cardiac grafts in pre-sensitised rats and concordant xenotransplantation

Immunosuppression in transplantation

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