Immunotherapy with OX40L-Fc or anti-CTLA-4 enhances local tissue responses and killing of Leishmania donovani.
Zubairi, Soombul;
Sanos, Stephanie L;
Hill, Sue;
Kaye, Paul M;
(2004)
Immunotherapy with OX40L-Fc or anti-CTLA-4 enhances local tissue responses and killing of Leishmania donovani.
European journal of immunology, 34 (5).
pp. 1433-1440.
ISSN 0014-2980
DOI: https://doi.org/10.1002/eji.200324021
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Enhancing granuloma development and effector function, but without inducing the pathology associated with excess granulomatous inflammation, poses a major challenge for immunotherapeutic intervention against diseases such as visceral leishmaniasis (VL). Here, we demonstrate that a chimeric fusion protein (OX40L-Fc) which stimulates T cells through OX40 and a monoclonal antibody which blocks CTLA-4, an inhibitory receptor on T cells, both enhanced the rate of granuloma maturation, CD4(+) T cell proliferation, and killing of Leishmania. Costimulation-based therapy induced no adverse fibrotic or necrotic reactions, and had no significant effect on the levels of endogenous anti-inflammatory cytokines (IL-10 and TGF-beta). Furthermore, both OX40L-Fc and anti-CTLA4 could be co-administered with conventional anti-leishmanial drugs. Until now, enhancing T cell immunity by the manipulation of costimulatory pathways has only received serious attention for cancer immunotherapy, but our data provide a compelling argument for the evaluation of this approach in human VL and other infectious diseases.