Response to Comment on “Aneurysmal Lesions of Patients with Abdominal Aortic Aneurysm Contain Clonally Expanded T Cells”

We appreciate Dr. Kroon and Dr. Taanman’s interest and comments on our manuscript demonstrating the presence of clonally expanded T cells in aneurysmal lesions of patients with aortic abdominal aneurysm (AAA) (1). The current treatment modalities for AAA involve surgical treatment which reduces the risk of death from aneurysm rupture but does not eliminate the underlying disease process and does not prevent additional aneurysm formation. Effective noninvasive medical treatment of AAA is not currently available. However, few potential therapeutic agents have been mentioned (reviewed in Ref. 2). The most promising of them is perhaps a well-known antibiotic, doxycycline, a tetracycline and inhibitor of matrix metalloproteinases (MMP) (reviewed in Ref. 2). Several reports have suggested that doxycycline inhibits the growth/propagation of AAA in animal models of aneurysmal disease (reviewed in Ref. 2). Inhibition of MMP levels by doxycycline was also reported in patients with AAA (3–5), in addition to suppression of neutrophil content, inhibition of CD8 infiltrating T cells, reduction of the levels of granzyme A, the levels of IL-6, IL-8, IL-13 and G-CSF proteins, and the levels of the AP-1 and C/EBPAP regulators of these ILs (5).

We have demonstrated the presence of oligoclonal T cell populations in AAA lesions (1). PCR amplification followed by cloning and sequencing revealed the presence of multiple identical copies of β-chain TCR transcripts in AAA lesions of these patients. Because of the large size of the T cell repertoire, the presence of identical copies of TCR transcripts in an independent sample of T cells cannot be explained by other mechanisms, except by specific Ag-driven proliferation and clonal expansion of T cell clones in response to as yet unidentified self- or nonself-Ag(s) or more correctly antigenic epitopes (reviewed in Ref. 6). Early-, intermediate- and late-activation Ags are expressed on mononuclear cells infiltrating AAA lesions (7), demonstrating that an active immune response is ongoing in these AAA lesions. Our work sets the stage for identifying the putative agent(s) underlying the process.

Doxycycline and/or other tetracyclines also act by arresting T cell proliferation in AAA lesions by inhibiting mitochondrial protein synthesis (8, 9) or suppressing NF of activated T cells in human CD4+ T cells (10), doxycycline inhibits also monocytes and granulocytes (5, 8, 9)

We agree with Drs. Koon and Taanman that doxycycline may be effective in inhibiting T cells in AAA as well as other autoimmune diseases where clonal expansions of T cells have been demonstrated and should be evaluated further for this purpose. However, these agents have been used only in patients with well-formed aneurysms. Earlier intervention will be needed to prevent aneurysm formation. Also, although doxycycline may control aneurysm growth, it does not stimulate repair of the aneurysm. Long-term treatment with doxycycline and other tetracylines should be evaluated in extensive clinical trials to determine whether they control the growth of the aneurysm, increase the time to surgery, and extend the survival of these patients.

• Copyright © 2014 by The American Association of Immunologists, Inc.