Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS).
Teachey DT, Obzut DA, Axsom K, Choi JK, Goldsmith KC, Hall J, Hulitt J, Manno CS, Maris JM, Rhodin N, Sullivan KE, Brown VI, Grupp SA.
University of PA School of Medicine/The Children's Hospital of Philadelphia.
Blood. 2006 Jun 6.

• > 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 high-frequency micro-ultrasound measurements (Vevo 660, VisualSonics) 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.