Scientists at the University Hospital of Ulm, Germany, have identified a mechanism by which the anti-TNF therapy, Remicade (Centocor), impairs host defense against tuberculosis. Their findings are published in the Journal of Clinical Investigation in a paper titled “Anti-TNF immunotherapy reduces CD8+ T cell mediated antimicrobial activity against Mycobacterium tuberculosis in humans.”
Anti-TNF therapies have been found to decrease the ability of the immune system to fight infections and have been associated with an increased incidence of tuberculosis. The researchers wanted to understand how these drug affect the immune system.
They hypothesized that anti-TNF immune therapy leads to an alteration of the adaptive T-cell response against M. tuberculosis, thereby triggering reactivation of latent tuberculosis. Given the key roles of perforin and granulysin in a T cell–mediated antimicrobial pathway, they initially studied expression of these proteins in patients receiving anti-TNF therapy.
They followed nine rheumatoid arthritis patients and eight ankylosing spondylitis patients and compared expression of perforin and granulysin in lymphocytes before the first drug infusion and before the second infusion two weeks later by intracellular flow cytometry.
During the course of immunotherapy, perforin and granulysin expression dropped significantly in all donors tested, indicating that the perforin/granulysin axis of antimicrobial activity was disturbed by anti-TNF treatment. The levels of perforin and granulysin expression in the peripheral blood of patients with autoimmune diseases was not significantly different compared with healthy donors.
The investigators thus reasoned that changes in lymphocyte subsets were responsible for the reduction of perforin+ and/or granulysin+ lymphocytes. They were able to pinpoint a subset of CD8-expressing effector memory immune T cells characterized by expression of these proteins. Furthermore, numbers of CD45RA+ effector memory CD8+ T cells were reduced in patients following treatment with Remicade.
As this correlated with a decreased ability of peripheral blood from the patients to kill M. tuberculosis, the authors conclude that the loss of this immune cell subset provides a mechanism to explain the reactivation of latent tuberculosis infection in some individuals being treated with Remicade.