Gamma delta T-lymphocytes sensitization to BCG vaccination is modulated by opiates

Mycobacterium tuberculosis remains a major burden worldwide attributing to approximately 3 million deaths annually. Mycobacterium bovis Bacille-Calmette-Guerin (BCG) is the only vaccine available sensitizing a cell mediated response capable of protecting humans against tuberculosis. Even with BCG-vaccination, tuberculosis progresses in some individuals to systemic or meningeal tuberculosis. Various factors including HIV infection and drugs of abuse contribute to the development of TB disease. The overall goal of this thesis was to characterize gamma delta (gammadelta) T-lymphocytes' response to BCG-vaccination and determine possible modulatory effects of morphine on gammadelta T-lymphocytes. To achieve this goal, a swine model was optimized enabling the characterization of gammadelta T-lymphocytes' response to BCG-vaccination. The characterization of gammadelta T-lymphocytes' response was accomplished by focusing on antigen directed proliferation, cytokine production, cytolytic responses, and delayed type hypersensitivity response to PPD administration following BCG-vaccination. This study revealed increased CMI responses following BCG vaccination. To fully characterize gammadelta T-lymphocytes response to BCG vaccination, we examined both total gammadelta T-lymphocytes' population and gammadelta T-lymphocytes' subsets (gammadelta/CD8-CD4 +, gammadelta/CD8+CD4-, gammadelta/CD8 -CD4-) responses to BCG-vaccination. gammadelta T-lymphocytes and their subpopulations proliferated and produced IFN-gamma following antigen stimulation, as well as increased in natural killer activity and antigen directed cytolytic activity against M. bovis infected monocytes. Meningitis remains the most lethal form of tuberculosis particularly in children. M. tuberculosis is capable of infecting microglia, the CNS macrophage. By incubating (gammadelta) T lymphocytes with M. bovis infected microglia, gammadelta T-lymphocytes proliferated, produced IFN-gamma, and demonstrated an increase in cytolytic activity. It was concluded that gammadelta T-lymphocytes' respond to Mycobacterium infected CNS targets. To investigate gammadelta T-lymphocytes susceptibility to potential modulatory effects of morphine, a well characterized swine model for immune alterations by morphine was used. gammadelta T-lymphocytes response to BCG-vaccination was significantly suppressed in morphine recipients. Treating microglia with morphine in-vitro altered gammadelta T-lymphocytes' response to M. bovis infected microglia. The overall conclusions from this thesis were gammadelta T-lymphocytes respond to BCG-vaccination in the periphery and against CNS targets, and are susceptible to opiate modulatory effects.