Synergistic effect of rapamycin and cyclosporin A in the treatment of experimental autoimmune uveoretinitis
Abstract
Immunosuppressive drugs currently available for the treatment of autoimmune diseases display a narrow therapeutic window between efficacy and toxic side effects. The use of combinations of drugs that have a synergistic effect may expand this window and reduce the risk of toxicity. We evaluated the combination effect of rapamycin (Rapa) and cyclosporin A (CsA) in an autoimmune disease model of the eye. The dose-effect relationship of Rapa with CsA was measured in vitro on the inhibition of proliferation of retinal S-Ag-primed lymphocytes. A median effect analysis was performed and a combination index (CI) calculated for 50% inhibition of proliferation. Rapa and CsA were markedly synergistic over a wide dose range (lowest CI = 0.31). Calculated dose reduction factors indicated that Rapa could be reduced nine-fold and CsA reduced five-fold when these drugs were used in combination. These reduced doses were tested in vivo for the treatment of experimental autoimmune uveoretinitis (EAU). Twelve of 15 rats treated with CsA, 2 mg/kg/day, developed EAU with a median severity of 2.5. Fourteen of 15 rats treated with Rapa, 0.01 mg/kg/day, developed EAU with a median severity of 3.25. Complete inhibition of EAU was achieved in all 15 animals treated with the combination of Rapa and CsA (combined vs CsA alone, p < 0.0002; combined vs Rapa alone, p < 0.00001). The demonstrated synergistic relationship between Rapa and CsA will allow the use of reduced doses of each drug to achieve a therapeutic effect. The use of lower doses may reduce the toxicity of these drugs for the treatment of autoimmune uveitis.
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The usage of cyclosporine, rapamycin, or daclizumab for uveitis is based on its effectiveness in experimental autoimmune uveitis.
“the usage of cyclosporine, rapamycin, or daclizumab for uveitis is based on its effectiveness in experimental autoimmune uveitis”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Martin et al., 1995
There are successful therapies for human disease that arose from mouse models.
“there are successful therapies for human disease that arose from mouse models”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Martin et al., 1995
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- Authors
- Martin, D. F., DeBarge, L. R., Nussenblatt, R. B., Chan, C. C., & Roberge, F. G.
- Affiliations
- National Institutes of Health (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 1995-01
- Volume
- 154
- Issue
- 2
- Pages
- 922-927
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1497273491
- Cited by
- 63
- References
- 0
- Citations by year
- 2022: 1 · 2020: 2 · 2019: 3 · 2017: 2 · 2016: 4 · 2015: 3 · 2013: 3 · 2012: 2
- FWCI
- 9.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Health Sciences › Medicine › Ophthalmology › Drug-Induced Ocular Toxicity
- Keywords
- rapamycin, cyclosporine, experimental autoimmune uveoretinitis, drug synergy, combination immunosuppressive therapy, autoimmune uveitis, dose reduction, combination index, mTOR inhibition
- MeSH terms
- Animals, Antigens, Autoimmune Diseases, Drug Synergism, Eye Proteins, Immunosuppressive Agents, Lymph Nodes, Lymphocyte Activation, Male, Polyenes, Rats, Inbred Lew, Retinitis, Uveitis, Cyclosporine, Arrestin, Sirolimus, Rats
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