CLINICAL STUDY
Oral tolerance with heat shock protein 65 attenuates mycobacterium tuberculosis-inducedand high-fat-diet-driven atherosclerotic lesions
Dror Harats, MD* ,*,
Niva Yacov, BSc,
Boris Gilburd, PhD ,
Yehuda Shoenfeld, MD and
Jacob George, MD
* Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer, Israel
Vascular Biogenics Ltd., Or-Yehuda, Israel
The Research Unit of Autoimmune Diseases, Sheba Medical Center, Sheba, Israel
Department of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
Manuscript received April 25, 2001;
revised manuscript received May 30, 2002,
accepted June 27, 2002.
* Reprint requests and correspondence: Dr. Dror Harats, Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel-Hashomer, 52621 Israel.
dharats{at}post.tau.ac.il
OBJECTIVES: The goal of this study was to explore the efficacy of oral tolerance with heat shock protein (HSP) 65 in two apparently non-overlapping models of murine atherosclerosis.
BACKGROUND: Atherosclerosis is considered to be a chronic inflammatory process. Autoimmune mechanisms have been shown to influence atherogenesis in experimental animal models. Heat shock protein 65 is a candidate antigen thought to drive a proatherogenic immune-mediated response. Mucosal tolerance is a therapeutic means of accomplishing immune unresponsiveness toward a given antigen by feeding it before active induction of the disorder.
METHODS: Low-density lipoprotein receptor deficient mice were fed with different doses of HSP65 every other day for 10 days. Feeding with either bovine serum albumin (BSA) or phosphate buffered saline (PBS) served as control. One day after the last feeding, mice were challenged either by immunization with heat killed Mycobacterium tuberculosis or by a high fat diet.
RESULTS: Lymphocyte reactivity from mice fed with HSP65 and immunized either against HSP65 or M. tuberculosis was significantly reduced in comparison with BSA-fed mice. Moreover, co-incubation of splenocytes—from mice with tolerance induced with HSP65 but not BSA—with HSP65-reactive lymphocytes resulted in the suppression of HSP65 reactivity by the latter cells. Interleukin-4 production by HSP65-fed and immunized mice was increased upon priming with respective protein. Early atherosclerosis was attenuated in HSP65-fed mice, compared with either BSA- or PBS-fed mice, regardless of the method employed to induce fatty streaks (M. tuberculosis immunization or high-fat diet).
CONCLUSIONS: Oral tolerance induced with HSP65 could prove to be a novel means of suppressing atherogenesis.
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Abbreviations and Acronyms
| | BSA | | bovine serum albumin | | ELISA | | enzyme-linked immunosorbent assay | | HSP | | heat shock protein | IFN- | | interferon-gamma | | IL-4 | | interleukin-4 | | LDL-RD | | low-density lipoprotein receptor deficient | | PBS | | phosphate buffered saline | | TGF-ß | | tumor growth factor-beta | | Th | | T helper |
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