Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS).

Abstract:

: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 patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that 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 enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. 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.

journal_name

Blood

journal_title

Blood

authors

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

doi

10.1182/blood-2006-01-010124

subject

Has Abstract

pub_date

2006-09-15 00:00:00

pages

1965-71

issue

6

eissn

0006-4971

issn

1528-0020

pii

blood-2006-01-010124

journal_volume

108

pub_type

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