title: Clonal expansion of T cells in abdominal aortic aneurysm: a role for doxycycline as drug of choice?
abstract: Most reported studies with animal models of abdominal aortic aneurysm (AAA) and several studies with patients have suggested that doxycycline favourably modifies AAA; however, a recent large long-term clinical trial found that doxycycline did not limit aneurysm growth. Thus, there is currently no convincing evidence that doxycycline reduces AAA expansion. Here, we critically review the available experimental and clinical information about the effects of doxycycline when used as a pharmacological treatment for AAA. The view that AAA can be considered an autoimmune disease and the observation that AAA tissue shows clonal expansion of T cells is placed in the light of the well-known inhibition of mitochondrial protein synthesis by doxycycline. In T cell leukaemia animal models, this inhibitory effect of the antibiotic has been shown to impede T cell proliferation, resulting in complete tumour eradication. We suggest that the available evidence of doxycycline action on AAA is erroneously ascribed to its inhibition of matrix metalloproteinases (MMPs) by competitive binding of the zinc ion co-factor. Although competitive binding may explain the inhibition of proteolytic activity, it does not explain the observed decreases of MMP mRNA levels. We propose that the observed effects of doxycycline are secondary to inhibition of mitochondrial protein synthesis. Provided that serum doxycycline levels are kept at adequate levels, the inhibition will result in a proliferation arrest, especially of clonally expanding T cells. This, in turn, leads to the decrease of proinflammatory cytokines that are normally generated by these cells. The drastic change in cell type composition may explain the changes in MMP mRNA and protein levels in the tissue samples.
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK. amk@keab.nl.
authors.forename: Albert M
authors.initials: AM
authors.lastname: Kroon
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK. j.taanman@ucl.ac.uk.
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D020782:Matrix Metalloproteinases; D004318:Doxycycline
keywords: T cells; abdominal aortic aneurysm (AAA); clonal expansion; doxycycline; drug target; matrix metalloproteinases; mitochondrial protein synthesis