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Blood, 15 September 2006, Vol. 108, No. 6, pp. 1965-1971.
Prepublished online as a Blood First Edition Paper on June 6, 2006; DOI 10.1182/blood-2006-01-010124.
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Submitted January 26, 2006
Accepted May 11, 2006
Rapamycin improves lymphoproliferative disease in murine
autoimmune lymphoproliferative syndrome (ALPS)
David T Teachey*, Dana A Obzut, Kelly Axsom, John K Choi, Kelly C Goldsmith, Junior Hall, Jessica Hulitt, Catherine S Manno, John M Maris, Nicholas Rhodin, Kathleen E Sullivan, Valerie I Brown, and Stephan A Grupp
University of PA School of Medicine/The Children's Hospital of Philadelphia
* Corresponding author; email: teacheyd{at}email.chop.edu.
Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double negative T cells (DNTs). Treatment options for ALPS patients are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by ELISA for anti-dsDNA antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at sacrifice (r=0.9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin treated mice to control. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.
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