Clinical Pharmacology & Biopharmaceutics
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It has been well established that the immune and neuroendocrine systems interact and communicate with each other. We have
demonstrated that methionine-enkephalin (Tyr-Gly-Gly-Phe-Met [YGGFM]) and certain of its peptide derivatives (Tyr-Gly-Gly
[YGG] and Tyr-Gly [YG]) modulate immune responses in a biphasic manner with suppression at high doses and enhancement at
low concentrations. These data showed in vivo (via DTH responses) and in vitro (via cytokine production) that met-enkephalin,
YGG and YG modulated immune responses in a concentration-dependent biphasic manner without affecting the overall number
of cells. The di and tri-peptides showed a higher specific activity than the parent molecule with YG being the smallest active moiety.
Tyr alone and GGFM were both inactive. Although YG and YGG were more potent than met-enkephalin in immune enhancement,
an analog of met-enkephalin resistant to peptidase activity [DADME] enhanced responses but did not induce suppression. Thus,
while cleavage of YGGFM to YG may be required for suppression it is not required for immune enhancement. Naloxone (an opioid
receptor antagonist) blocked enhancive but not suppressive effects of met-enkephalin. Thus, binding to classical opiate receptors may
be involved in the initiation of enhancement by met-enkephalin while cleavage to YG and an unidentified, nonopioid receptor may be
associated with suppression. This is consistent with negative feedback such that when the concentration of YG increases, a suppressor
mechanism downregulates the response. Thus, these studies may identify a novel mechanism heretofore unrecognized and given
that the enkephalins are conserved throughout nature, it may represent one of the oldest means of regulating immune responses in
Robert C Sizemore has received his PhD in Medical Microbiology & Immunology from the University of Louisville, School of Medicine. During his Post-doctoral research at the University of Mississippi Medical Center, he showed that fish have macrophages and that they act much like their mammalian counterparts. He has served as the Director of Immunology for a biotechnology firm (IMREG) that developed a treatment for AIDS. He is a Member of American Association of Immunologists, an Editor for Cell and Developmental Biology and a Member of the Advisory Board for the Penn State-ASU Bridges to the Doctorate Program. He has served on a Review Panel at the NIH and has over 50 published articles and abstracts and two patents.