Immunology

A total of 80 cases of Legionella pneumonia have been reported to the FDA among patients receiving TNFα inhibitors, most often for rheumatoid arthritis.

Median age of affected patients was 56.

Median duration of TNFα inhibitor treatment was 10.4 months, but cases occurred as early as within one month and as late as 73 months after beginning treatment.

Many of the patients were also being treated with methotrexate and corticosteroids, and 14 deaths occurred.

Thus far there also have been 23 published cases of Legionella pneumonia in patients ages 26 to 71, with three deaths.

In four of these cases, the pneumonia was severe enough to warrant mechanical ventilation, and in five cases, intensive care treatment was needed.

One patient had a second episode of Legionella pneumonia after treatment with the TNFα inhibitor was restarted.

There are also now 26 published cases of serious infections -- meningitis, endophthalmitis, bacteremia, and sepsis -- with Listeria monocytogenes in patients receiving these drugs.

Seven patients died of the infection.

In addition, FDA cautioned that Listeria infections also occurred during clinical trials of the TNFα inhibitors.

TCRαβ+CD3+CD4−CD8−NK1.1− double negative (DN) Tregs comprise 1–3% of peripheral T lymphocytes in mice and humans. It has been demonstrated that DN Tregs can suppress allo-, xeno- and auto-immune responses in an Ag-specific fashion. However, the mechanisms by which DN Tregs regulate immune responses remain elusive. Whether DN Tregs can regulate DCs has not been investigated previously. In this study, we demonstrate that DN Tregs express a high level of CTLA4 and are able to down-regulate costimulatory molecules CD80 and CD86 expressed on Ag-expressing mature DCs (mDCs). DN Tregs from CTLA4 KO mice were not able to downregulate CD80 and CD86 expression, indicating that CTLA4 is critical for DN Treg-mediated downregulation of costimulatory molecule expression on Ag-expressing mature DCs. Furthermore, DN Tregs could kill both immature and mature allogeneic DCs, as well as Ag-loaded syngeneic DCs, in an Ag-specific manner in vitro and in vivo, mainly through the Fas-FasL pathway. These data demonstrate, for the first time, that DN Tregs are potent regulators of DCs and may have the potential to be developed as a novel immune suppression treatment.