Treatment with Interleukin-7 Restores Host Defense against Pneumocystis in CD4+ T-Lymphocyte-Depleted Mice.
Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality in patients with HIV infection. CD4(+) T lymphocytes are critical for host defense against this infection, but in the absence of CD4(+) T lymphocytes, CD8(+) T lymphocytes may provide limited host defense. The cytokine interleukin-7 (IL-7) functions to enhance lymphocyte proliferation, survival, and recruitment of immune cells to sites of infection. However, there is little known about the role of IL-7 in PCP or its potential use as an immunotherapeutic agent. We hypothesized that treatment with recombinant human IL-7 (rhIL-7) would augment host defense against Pneumocystis and accelerate pathogen clearance in CD4-depleted mice. Control and CD4-depleted mice were infected with Pneumocystis, and rhIL-7 was administered via intraperitoneal injection. Our studies indicate that endogenous murine IL-7 is part of the normal host response to Pneumocystis murina and that administration of rhIL-7 markedly enhanced clearance of Pneumocystis in CD4-depleted mice. Additionally, we observed increased recruitment of CD8(+) T lymphocytes to the lungs and decreased apoptosis of pulmonary CD8(+) T lymphocytes in rhIL-7-treated animals compared to those in untreated mice. The antiapoptotic effect of rhIL-7 was associated with increased levels of Bcl-2 protein in T lymphocytes. rhIL-7 immunotherapy in CD4-depleted mice also increased the number of gamma interferon (IFN-γ)-positive CD8(+) central memory T lymphocytes in the lungs. We conclude that rhIL-7 has a potent therapeutic effect in the treatment of murine Pneumocystis pneumonia in CD4-depleted mice. This therapeutic effect is mediated through enhanced recruitment of CD8(+) T cells and decreased apoptosis of lung T lymphocytes, with a preferential action on central memory CD8(+) T lymphocytes.
Section of Pulmonary/Critical Care & Allergy/Immunology, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA sruan1@lsuhsc.edu.
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Ruan
Section of Pulmonary/Critical Care & Allergy/Immunology, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
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Samuelson
Cytheris SA, Technopolis, Issy Les Moulineaux, France.
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Assouline
Cytheris SA, Technopolis, Issy Les Moulineaux, France.
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M
Morre
Section of Pulmonary/Critical Care & Allergy/Immunology, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
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Shellito
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D007371:Interferon-gamma / Q000276:immunology; D015851:Interleukin-7 / Q000627:therapeutic use*; D008168:Lung / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D011010:Pneumocystis / Q000276:immunology / Q000472:pathogenicity; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use
C508605:IL7 protein, human; D015851:Interleukin-7; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D007371:Interferon-gamma