Ustianowski, Andrew Peter; (2001) Biological studies on heat-killed mycobacterium vaccae. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A preparation of heat-killed Mycobacterium vaccae (SRL-172) is being investigated as a potential immunotherapeutic in mycobacterial infections, allergies, cancers, malaria, vascular disease, psoriasis, periodontal disease and other conditions. The potential effects of this agent upon specific lymphocyte subsets in vitro and humoral responses to the 60/65 kDa heat shock protein (hsp60/65) family in vivo were investigated. Flow cytometric assessment of proliferation, activation marker expression (CD25, HLA-DR, CD69, CD80 and CD86) and production of the cytokines IFN-y and LL-4 was performed after the incubation of freshly isolated peripheral blood mononuclear cells with dilutions of heat-killed M. vaccae. T lymphocytes were assessed in experiments incorporating incubation with isopentenyl pyrophosphate, PPD and exogenous IL-2. Results demonstrated an influence on proliferation, CD25, CD69 and CD86 expression and cytokine production in lymphocytes and proliferation, CD25 and CD69 expression in CD56+ NK lymphocytes. No significant effects on (CD56+ CD3+) NKT cells were demonstrated. The majority of the gene for the M. vaccae hsp65 molecule was sequenced (for comparison with the human and known mycobacterial homologues, specifically with relation to epitopes implicated in autoimmune and other conditions) and the antibody titres to the human hsp60 molecule (including fragments there-of) and the M. bovis hsp65 protein were assessed in both rats and humans that had received placebo or combinations of immunisations including SRL-172. DNA sequence comparisons failed to highlight specific epitopes that may be implicated in the efficacy of SRL-172, but ELISA assays demonstrated a relative increase in IgG2a titres to the human (but not the mycobacterial) hsp60/65 protein in rats that had received SRL-172 prior to hsp65 immunisation, and a correlation between aortic contractility and IgG2a titres to human hsp60 in rodents that received both hsp65 and high-dose SRL-172 vaccination. This work has increased the knowledge of the immunology behind this promising immunotherapeutic and suggested several areas for further research.

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