Both immunity and hyperresponsiveness to Pneumocystis carinii result from transfer of CD4+ but not CD8+ T cells into severe combined immunodeficiency mice.

Roths, John B.; Sidman, Charles L.

doi:10.1172/jci115910

Cited by 150 publications

(145 citation statements)

References 32 publications

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“…Consistent with previously published studies (16,17,30,33,39), our studies show that CD4 ϩ T cells are absolutely essential to clear the P. carinii infection. It is possible that features of CD4 function that are essential for P. carinii clearance are also responsible for inflammatory lung injury.…”

Section: Discussionsupporting

confidence: 93%

“…Using a murine model of IRD, the contribution of individual lymphocyte subsets was studied by selective depletion using specific MAb. Our results not only confirmed that CD4 ϩ T cells are critical for P. carinii-clearance (16,30,34,39), but also demonstrated that they directly contribute to the severe lung injury associated with IRD. Furthermore, our results show that CD8 ϩ T cells also play a dual role during PcP: an immune-modulatory role in the presence of CD4 ϩ T cells, and an inflammatory, nonprotective role in the absence of CD4 ϩ T cells.…”

Section: Discussionsupporting

confidence: 81%

mentioning

confidence: 99%

“…Although exposure to P. carinii is nearly universal, as demonstrated by the appearance of anti-P. carinii antibody in 85% of children by the age of 20 mo (35), a period of immunosuppression is essential for the development of clinical disease (15,34). Several studies have demonstrated a positive correlation between the degree of inflammation and the severity of disease (4,23,36), suggesting that the pathogenesis of Pneumocystis pneumonia (PcP) is primarily inflammatory in nature, in that infection with P. carinii is necessary to cause pneumonia, but certain aspects of the immune response against P. carinii are responsible for the associated pathophysiology (30,39). For example, AIDS patients who demonstrate a rapid recovery of CD4 ϩ T lymphocytes after institution of combined antiretroviral therapy may develop pulmonary decompensation in response to preexisting pulmonary infections, including P. carinii (26).…”

mentioning

confidence: 99%

“…Whereas the contribution of CD4 ϩ T cells (17,31,33), TNF-␣ (7), and IL-1 (8) to P. carinii clearance has been established in this IRD model, the specific contributions of CD4 ϩ and CD8 ϩ T cells to the pathological response associated with IRD remains unknown. Work from several groups (17,30) noted that the transfer of flow-sorted CD4 ϩ cells from P. carinii-immunized donors to heavily infected SCID mice could induce a lethal hyperinflammatory response, suggesting that CD4 ϩ T cells could contribute to immune-mediated pathology if sensitized by prior exposure to P. carinii. In addition, recent studies have demonstrated that the severity of IRD can be alleviated by the transfer of CD25 ϩ /CD4 ϩ T regulatory cells (18) or the delivery of viral IL-10 to the lung (32).…”

mentioning

confidence: 99%

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Contribution of T cell subsets to the pathophysiology ofPneumocystis-related immunorestitution disease

Bhagwat

Gigliotti²,

Xu³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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.-Immune-mediated lung injury is an important component of Pneumocystis pneumonia (PcP)-related immunorestitution disease (IRD). However, the individual contribution of CD4 ϩ and CD8 ϩ T cells to the pathophysiology of IRD remains undetermined. Therefore, IRD was modeled in severe combined immunodeficient mice, and specific T cell depletion was used to determine how T cell subsets interact to affect the nature and severity of disease. CD4 ϩ cells were more abundant than CD8 ϩ cells during the acute stage of IRD that coincided with impaired pulmonary physiology and organism clearance. Conversely, CD8 ϩ cells were more abundant during the resolution phase following P. carinii clearance. Depletion of CD4 ϩ T cells protected mice from the acute pathophysiology of IRD. However, these mice could not clear the infection and developed severe PcP at later time points when a pathological CD8 ϩ T cell response was observed. In contrast, mice depleted of CD8 ϩ T cells efficiently cleared the infection but developed more severe disease, an increased frequency of IFN-␥-producing CD4 ϩ cells, and a prolonged CD4 ϩ T cell response than mice with both CD4 ϩ and CD8 ϩ cells. These data suggest that CD4 ϩ T cells mediate the acute respiratory disease associated with IRD. In contrast, CD8 ϩ T cells contributed to neither lung injury nor organism clearance when CD4 ϩ cells were present, but instead served to modulate CD4 function. In the absence of CD4 ϩ cells, CD8 ϩ T cells produced a nonprotective, pathological immune response. These data suggest that the interplay of CD4 ϩ and CD8 ϩ T cells affects the ultimate outcome of PcP-related IRD.inflammation; pulmonary physiology; acquired immune deficiency syndrome PNEUMOCYSTIS carinii IS an opportunistic fungus that causes pneumonia in immune-compromised patients (37), including patients with acquired immune deficiency syndrome (AIDS) (29), patients undergoing chemotherapy, and patients receiving treatment with immunosuppressive drugs during organ transplantation (34). Although exposure to P. carinii is nearly universal, as demonstrated by the appearance of anti-P. carinii antibody in 85% of children by the age of 20 mo (35), a period of immunosuppression is essential for the development of clinical disease (15,34). Several studies have demonstrated a positive correlation between the degree of inflammation and the severity of disease (4,23,36), suggesting that the pathogenesis of Pneumocystis pneumonia (PcP) is primarily inflammatory in nature, in that infection with P. carinii is necessary to cause pneumonia, but certain aspects of the immune response against P. carinii are responsible for the associated pathophysiology (30, 39). For example, AIDS patients who demonstrate a rapid recovery of CD4 ϩ T lymphocytes after institution of combined antiretroviral therapy may develop pulmonary decompensation in response to preexisting pulmonary infections, including P. carinii (26). This clinical syndrome has been termed "immunorestitution disease" (IRD) (9). At least one study that examined t...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 81%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Contribution of T cell subsets to the pathophysiology ofPneumocystis-related immunorestitution disease

Bhagwat

Gigliotti²,

Xu³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Fulminant Pneumocystis carinii Pneumonia in 4 Patients With Dermatomyositis

Bachelez

Schremmer²,

Cadranel³

et al. 1997

Arch Intern Med

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Between 1989 and 1996, 4 cases of Pneumocystis carinii pneumonia (PCP) were observed in patients seronegative for the human immunodeficiency virus who were receiving corticosteroid therapy for dermatomyositis in our institution. These cases were considered unusual in light of the short delay of their onset after initiation of immunosuppressive therapy and their fulminant course: 3 of these patients died of PCP occurring during the first month of treatment with prednisone. In all 4 patients lymphopenia was observed before the initiation of corticosteroid treatment and low CD4 and CD8 cell counts were evident at the time of PCP. These observations support the view of an increase in both the severity and incidence of PCP in patients without human immunodeficiency virus infection and question the need for a primary prophylaxis in patients with connective tissue diseases receiving high-dose corticosteroid therapy.

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Effect on parasite eradication ofPneumocystis carinii-specific antibodies produced in the presence or absence of CD4+ α β T lymphocytes

Hanano¹,

Kaufmann²

1999

Eur. J. Immunol.

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The contribution of specific antibodies (Ab) to successful clearance of Pneumocystis carinii from host pulmonary tissues has received increasing attention. Sera collected from diseased recombinase‐activating gene (RAG)‐1–/–, TCRβxδ–/–, TCRβ–/– and Aβ–/– mutants as well as from aerogenic parasite‐exposed (aero) and intranasally (i. n.) infected C57BL/6 mice were transferred to RAG‐1–/– mutants inoculated with freshly isolated parasites. All sera, except for RAG‐1–/– serum, contained P. carinii‐specific Ab of varying isotype concentrations. Four weeks after serum treatment pulmonary parasite numbers were reduced slightly by Aβ–/– and C57BL/6‐aero sera, and markedly by TCRβ–/– and C57BL/6‐i. n. sera. Our data reveal: (1) T cells are essential, and CD4+ T cells are important for formation of protective Ab; (2) at least in the absence of α β T cells, γ δ T cells provide help for protective Ab. In vitro treatment of bronchoalveolar lavage cells with the different sera largely led to comparable results. Opsonizing Ab impeding parasite attachment to host cells, as well as Ab possibly neutralizing parasite‐secreted products were implicated. Furthermore, serum components other than Abappear to participate in resistance to fungal manifestation.

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Both immunity and hyperresponsiveness to Pneumocystis carinii result from transfer of CD4+ but not CD8+ T cells into severe combined immunodeficiency mice.

Cited by 150 publications

References 32 publications

Contribution of T cell subsets to the pathophysiology ofPneumocystis-related immunorestitution disease

Contribution of T cell subsets to the pathophysiology ofPneumocystis-related immunorestitution disease

Fulminant Pneumocystis carinii Pneumonia in 4 Patients With Dermatomyositis

Effect on parasite eradication ofPneumocystis carinii-specific antibodies produced in the presence or absence of CD4+ α β T lymphocytes

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