Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus.
OBJECTIVE
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. Current treatment options are often ineffective or poorly tolerated. Recent observations have revealed mitochondrial hyperpolarization and enhanced Ca2+ fluxing in T cells from SLE patients. Rapamycin, a lipophilic macrolide antibiotic that regulates mitochondrial transmembrane potential and Ca2+ fluxing, has been used safely and effectively to treat renal transplant rejection since 1999. In addition, rapamycin has been shown to ameliorate T cell function and to prolong survival in lupus-prone MRL/lpr mice. We therefore undertook the present study to investigate whether rapamycin is beneficial in patients with SLE.


METHODS
Nine patients with clinically active SLE that had been treated unsuccessfully with other immunosuppressive medications began therapy with rapamycin, 2 mg/day orally. Disease activity was assessed with the British Isles Lupus Assessment Group (BILAG) score, SLE Disease Activity Index (SLEDAI), and requirement for prednisone therapy. Mitochondrial transmembrane potential and Ca2+ fluxing were assessed by flow cytometry.


RESULTS
In patients treated with rapamycin, the BILAG score was reduced by a mean +/- SEM of 1.93 +/- 0.9 (P = 0.0218), the SLEDAI by 5.3 +/- 0.8 (P = 0.00002), and concurrent prednisone use by 26.4 +/- 6.7 mg/day (P = 0.0062) compared with pre-rapamycin treatment. While mitochondrial hyperpolarization persisted, pretreatment cytosolic and mitochondrial Ca2+ levels and T cell activation-induced rapid Ca2+ fluxing were normalized in rapamycin-treated patients.


CONCLUSIONS
Rapamycin appears to be a safe and effective therapy for SLE that has been refractory to traditional medications. Mitochondrial dysfunction and Ca2+ fluxing could serve as biomarkers to guide decisions regarding future therapeutic interventions in SLE.
Fernandez
David
D
State University of New York, Syracuse, NY 13210, USA.
Bonilla
Eduardo
E
Mirza
Naureen
N
Niland
Brian
B
Perl
Andras
A
D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D018929:Cell Culture Techniques; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D020123:Sirolimus