Decrease in a T-cell subset may explain the reactivation of latent tuberculosis in patients treated with anti-TNF drugs
The introduction of the new biological therapies have revolutionized the treatment of patients with several inflammatory diseases (such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis) biological therapies inflammatory bowel disease. While these therapies have proven efficacy, they are not without significant side effects due to their actions on the immune system, increasing the possibility of the patients to develop several types of infections and neoplasms.
Among the most effective in treating psoriasis are several drugs that target the cytokine protein TNF, such as infliximab, adalimumab, and etanercept. These drugs have collectively been called anti-TNF therapies, and one of the main concerns (with the monoclonal antibodies against TNF, infliximab and adalimumab, in particular) is that these patients have a higher incidence of tuberculosis than the general population. This makes mandatory to perform latent tuberculosis screening in patients with psoriasis who are planned to be treated with these drugs.
In a recent study published in the May 2009 issue of the Journal of Clinical Investigation, a group of German researchers investigated the immune cells of patients with rheumatoid arthritis before and after treatment with infliximab to try and identify the mechanisms underlying the association between anti-TNF therapy and tuberculosis. The authors found that anti-TNF therapy reduced lymphocyte expression of perforin and granulysin, two components of the T cell-mediated antimicrobial response to intracellular pathogens. They found that subset of effector memory CD8+ T cells characterized by the expression of the protein CD45RA expressed the highest levels of granulysin. The authors called these CD8+CCR7–CD45RA+ effector memory T cells “TEMRA cells”.
TEMRA cells were found to lyse Mycobacterium tuberculosis and infected macrophages, and mediate an antimicrobial attack against M. tuberculosis. They also express membrane TNF and bind to anti-TNF antibodies. During the first 2 weeks of treatment with infliximab TEMRA cells decreased by an average of 29%. Moreover, monocytes isolated from patients and infected with M. tuberculosis showed that peripheral blood mononuclear cells limited bacterial growth more efficiently before than during infliximab therapy. When peripheral blood mononuclear cells from infliximab-treated patients were replenished with autologous TEMRA cells their ability to limit M. tuberculosis growth was restored.
The authors conclude that the loss of this immune cell subset provides a mechanism to explain the reactivation of latent tuberculosis infection in patients treated with infliximab.
Anti-TNF immunotherapy reduces CD8+ T cell–mediated antimicrobial activity against Mycobacterium tuberculosis in humans
Bruns H et al.
J Clin Invest 2009; 119:1167–1177.
The incidence of tuberculosis is increased during treatment of autoimmune diseases with anti-TNF antibodies. This is a significant clinical complication, but also provides a unique model to study immune mechanisms in human tuberculosis. Given the key role for cell-mediated immunity in host defense against Mycobacterium tuberculosis, we hypothesized that anti-TNF treatment impairs T cell–directed antimicrobial activity. Anti-TNF therapy reduced the expression in lymphocytes of perforin and granulysin, 2 components of the T cell–mediated
