Cyclosporine Therapy for Autoimmune Disease

Cg, Fathman; Bd, Myers

doi:10.1056/nejm199206183262509

Cited by 55 publications

(14 citation statements)

References 9 publications

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“…Thus CsAtreated patients can reject allografts (54), express abundant T cell cytokines (55), and be immunized against exogenous antigens (56). The effectiveness of CsA, evident by the reduction in allograft rejection rates (57) and the successful treatment of some autoimmune disorders (58), is due to the reduction in CN activity and its subsequent quantitative (and qualitative?) effect on immune responses.…”

Section: Discussionmentioning

confidence: 99%

Evidence that calcineurin is rate-limiting for primary human lymphocyte activation.

Batiuk

Kung²,

Halloran³

1997

J. Clin. Invest.

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Cyclosporine (CsA) is both a clinical immunosuppressive drug and a probe to dissect intracellular signaling pathways. In vitro, CsA inhibits lymphocyte gene activation by inhibiting the phosphatase activity of calcineurin (CN). In clinical use, CsA treatment inhibits 50-75% of CN activity in circulating leukocytes. We modeled this degree of CN inhibition in primary human leukocytes in vitro in order to study the effect of partial CN inhibition on the downstream signaling events that lead to gene activation. In CsA-treated leukocytes stimulated by calcium ionophore, the degree of reduction in CN activity was accompanied by a similar degree of inhibition of each event tested: dephosphorylation of nuclear factor of activated T cell proteins, nuclear DNA binding, activation of a transfected reporter gene construct, IFN-␥ and IL-2 mRNA accumulation, and IFN-␥ production. Furthermore, the degree of CN inhibition was reflected by a similar degree of reduction in lymphocyte proliferation and IFN-␥ production in the allogeneic mixed lymphocyte cultures. These data support the conclusion that CN activity is rate-limiting for the activation of primary human T lymphocytes. Thus, the reduction of CN activity observed in CsA-treated patients is accompanied by a similar degree of reduction in lymphocyte gene activation, and accounts for the immunosuppression observed. ( J. Clin. Invest. 1997.

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Section: Discussionmentioning

confidence: 99%

Evidence that calcineurin is rate-limiting for primary human lymphocyte activation.

Batiuk

Kung²,

Halloran³

1997

J. Clin. Invest.

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“…The discovery of the immunosuppressive properties of cyclosporin A (CSA) initiated a new era in immunopharmacology [1]and today it is still the major drug used for preventing graft rejection and autoimmune diseases [2]. More recently, its use was also proposed in the treatment of resistant tumors, due to its ability to reverse multidrug resistance (MDR) phenotype [3].…”

Section: Introductionmentioning

confidence: 99%

Comparative Study on the Effects of Cyclosporin A in Renal Cells in Culture

Nascimento

Braga

Capella

et al. 2005

Nephron Exp Nephrol

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Background: Although cyclosporin A (CSA) inhibits P-glycoprotein (ABCB1), the relationship between this inhibition and CSA-induced nephrotoxicity is not established. Methods: Three renal cell lines were used to investigate the effects of CSA in cellular viability and accumulation of rhodamine 123 (Rho123): LLC-PK1, which does not express ABCB1 substantially; MDCK, expressing moderate amounts of this protein, and Ma104 cells, which express high amounts of ABCB1. Results: The viability was significantly reduced in the three cell lines after treatment with CSA concentrations >10 µM. Ma104 was the more resistant and LLC-PK1 the more sensitive. CSA increased Rho123 accumulation in the three cell lines when incubated simultaneously, MDCK presenting the higher increase. However, different results were achieved when the periods of incubation with Rho123 and CSA were disconnected: a post-incubation with CSA was more effective in Ma104 cells, while MDCK and LLC-PK1 showed no difference between pre-, co- and post-incubation with CSA. Conclusions: Our results suggest that the effects of CSA may be divided into two groups: ABCB1-independent (direct injury), and ABCB1-dependent toxicity, due to modulation of its activity. This could result in increased accumulation of noxious ABCB1 substrates, contributing to CSA-induced nephrotoxicity. Furthermore, the mechanisms of ABCB1 modulation by CSA may be different for different cell lines.

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“…These patients are offered splenectomy, which removes the destruction site of antibody–coated RBCs adhering to splenic macrophages via Fc receptors [26]. In resistant cases, intravenous immunoglobulins (IVIG) [8, 27]and cyclosporin A [28]have been used. Cyclosporin A has been used in PRCA with an overall response rate of 65% [28].…”

Section: Discussionmentioning

confidence: 99%

“…In resistant cases, intravenous immunoglobulins (IVIG) [8, 27]and cyclosporin A [28]have been used. Cyclosporin A has been used in PRCA with an overall response rate of 65% [28]. Its main action is the inhibition of cytokine production by T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Splenic Lymphoma Presenting as Warm Autoimmune Hemolytic Anemia Associated with Pure Red Cell Aplasia

Zeidman¹,

Fradin²,

Barac

et al. 2000

Vox Sanguinis

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Background and Objective: Warm autoimmune hemolytic anemia (AIHA) is a condition in which peripheral red blood cell (RBC) destruction is induced by the presence of an autoantibody. Pure red cell aplasia (PRCA) represents an isolated process of decreased erythropoiesis. The combination of both is quite rare, with a very poor prognosis. We describe a patient with isolated splenic lymphoma whose presentation was a combination of AIHA and PRCA. The patient was resistant to all treatment. Materials and Methods: Erythroid colony assays were performed, in order to compare the effect of the patient's serum on colonies with that of a normal control. Results: The patient's serum significantly suppressed normal erythroid colony growth. A red cell eluate revealed the presence of a warm autoantibody. Conclusions: The patient's serum contained warm autoantibody responsible for peripheral RBC destruction and a humoral factor, perhaps the warm autoantibody, which suppressed bone marrow erythropoiesis. Establishing an early diagnosis, and treatment of the underlying disease might result in a better prognosis.

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Cyclosporine Therapy for Autoimmune Disease

Cited by 55 publications

References 9 publications

Evidence that calcineurin is rate-limiting for primary human lymphocyte activation.

Evidence that calcineurin is rate-limiting for primary human lymphocyte activation.

Comparative Study on the Effects of Cyclosporin A in Renal Cells in Culture

Splenic Lymphoma Presenting as Warm Autoimmune Hemolytic Anemia Associated with Pure Red Cell Aplasia

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