Anti-CD3 antibody decreases inflammation and improves outcome in a murine model of Pneumocystis pneumonia.
The T cell-mediated immune response elicited by Pneumocystis plays a key role in pulmonary damage and dysfunction during Pneumocystis carinii pneumonia (PcP). Mice depleted of CD4(+) and CD8(+) T cells prior to infection are markedly protected from PcP-related respiratory deficit and death, despite progressive lung infection. However, the therapeutic effectiveness of Ab-mediated disruption of T cell function in mice already displaying clinical symptoms of disease has not been determined. Therefore, a murine model of PcP-related immune reconstitution inflammatory syndrome was used to assess whether Ab to the pan-T cell molecule CD3 is effective for reducing the severity of PcP when administered after the onset of disease. Mice that received anti-CD3 Ab exhibited a rapid and dramatic halt in the PcP-associated pulmonary function decline within 1 week after treatment, and a striking enhancement of survival rate compared with mice receiving the control Ab. Physiologic improvement in anti-CD3 treated mice was associated with a significant reduction in the number of CD4(+) and CD8(+) T cells recovered in lung lavage fluid. This effectiveness of anti-CD3 was noted whether the mice also received antibiotic therapy with trimethoprim-sulfamethoxazole. These data suggest that monoclonal Ab-mediated disruption of T cell function may represent a specific and effective adjunctive therapy to rapidly reverse the ongoing pathologic immune response occurring during active PcP. Thus, the anti-human CD3 monoclonal Ab OKT3, which is already in clinical use, has the potential to be developed as an adjunctive therapy for PcP.
Bhagwat
Samir P
SP
Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Wright
Terry W
TW
Gigliotti
Francis
F
D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use; D000906:Antibodies / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D008212:Lymphocyte Depletion / Q000379:methods*; D051379:Mice; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use
D000890:Anti-Infective Agents; D000906:Antibodies; D017252:CD3 Complex; D015662:Trimethoprim, Sulfamethoxazole Drug Combination