Biomedical subjects
Publications and source records attributed to Robert V Bundick.
One of the driving forces in the field of immunology is the ambition to translate experimental research into novel useful therapies. Therefore, the aim of this mini-review is to exemplify emerging therapies as well as highlight hurdles that need to be overcome before they can be introduced into the clinic.
Despite expanding use of drugs blocking tumour necrosis factor (TNF), their precise mechanisms of action remain unclear. Early assumptions that they act by direct neutralization of the toxic inflammatory effects of TNF might be too simplistic because they explain neither the range of effects observed nor the varying properties of different TNF-blocking agents. Recent studies have demonstrated a key role for mast cell-derived TNF in the increase in lymph node size and the organizational complexity that accompanies a developing immune response. Regulation of this phenomenon might comprise a novel mode of action for TNF-directed therapy: by preventing this lymph node hyperplasia, TNF blockade could modulate immune responses, ameliorating pathology in autoimmune diseases, such as rheumatoid arthritis.
Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1), using a strategy of photoaffinity labeling and proteomic characterization. We show that inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. MCT1 activity, however, is not required for many stages of lymphocyte activation, such as cytokine production, or for most normal physiological functions. By pursuing a chemistry-led target identification strategy, we have discovered that MCT1 is a previously unknown target for immunosuppressive therapy and have uncovered an unsuspected role for MCT1 in immune biology.