Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Recombinant Chaperonin 10 Suppresses Cutaneous Lupus and Lupus Nephritis in MRL-(Fas)lpr Mice.

Kulkarni3,  Onkar P., Ryu3,  Mi, Kantner3,  Claudia, Sardy2,  Miklos, Naylor1,  Dean, Brown1,  Richard, Vanags1,  Daina

CBio Ltd, Eight Mile Plains, Queensland, Australia
Department of Dermatology and Allergology, University of Munich, Munich, Germany
Medizinische Poliklinik-Innenstadt, University of Munich, Munich, Germany

Purpose:

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder mostly affecting young females. The autoimmune disease manifestations are still treated with unspecific immunosuppressants such as steroids or cytotoxic drugs that cause serious toxicities. Since patients largely suffer from inflammatory tissue damage and not from autoimmunity per se, selective anti-inflammatory compounds may offer protection from tissue damage without causing immunosuppression.

Chaperonin 10 fulfills an essential role in mitochondrial protein folding and an extracellular role in immunomodulation suggesting potential therapeutic value for the treatment of inflammatory disorders1. Accordingly, in early phase II clinical studies in human patients the efficacy and safety of Cpn10 in treating signs and symptoms of rheumatoid arthritis2 and chronic plaque psoriasis (CPP)3 has been established. Here recombinant Cpn10 was examined for its' ability to additionally control the autoimmune manifestations of SLE.

Methods:

Female MRLlpr/lpr mice with lupus-like autoimmunity were given either Cpn10 (100mg/mouse, 5mg/kg) or placebo (Tris-buffred saline) by intraperitoneal injection every alternate day from 10 to 22 weeks of age. Clinical signs were recorded over the study period, and mortality was recorded every week throughout the study. Plasma samples were collected prior to sacrifice after 11 weeks of treatment. Urine samples were collected in week 22 of age. Tissue samples for histology were immediately fixed in formalin prior to paraffin fixation.

Results:

Cpn10 entirely prevented the lupus-like cutaneous lesions as compared to vehicle-treated MRLlpr/lpr mice as evident from macroscopy as well as from microscopical evaluation. Cpn10 also improved lupus nephritis as evident from serum creatinine levels, albuminuria, and the histomorpholocial scores of disease activity and chronicity (p<0.05). Autoimmune lung disease remained unaffected by Cpn10 treatment. However, Cpn10 prolonged overall survival of MRLlpr/lpr mice (90% survival vs. 65% for treated mice, p<0.05). The therapeutic potential of Cpn10 on skin and kidney disease was not associated with any significant effects on either T cell, dendritic cell or B cell counts in spleen, on plasma IFN-g, TNF-a or IL-10 levels, plasma DNA autoantibody levels or on markers of lymphoproliferation.

Conclusion:

Our study clearly demonstrates that Cpn10 prevents cutaneous lupus and suppresses lupus nephritis in MRLlpr/lpr mice without affecting the underlying autoimmune process or systemic inflammation. Hence, Cpn10 shows significant potential for the treatment of selective human SLE-related tissue pathologies, such as cutaneous lupus and lupus nephritis whilst possibly offering an improved safety profile by not blocking healthy immune responses. This work taken together with previously published data in human RA and CPP trials, provides evidence of Cpn10's utility beyond a single indication.

References:

1Johnston, B., et al. (2005). J. Biol. Chem 280, 4037-4047

2Vanags, D., et al. (2006). The Lancet 368, 855-863

3Williams, B., et al. (2008). Arch Dermatol 144, 683-684

To cite this abstract, please use the following information:
Kulkarni, Onkar P., Ryu, Mi, Kantner, Claudia, Sardy, Miklos, Naylor, Dean, Brown, Richard, et al; Recombinant Chaperonin 10 Suppresses Cutaneous Lupus and Lupus Nephritis in MRL-(Fas)lpr Mice. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :441
DOI: 10.1002/art.28210

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