Recombinant interleukin 2 therapy in severe combined immunodeficiency disease.

Pahwa, Rajendra; Chatila, Talal A.; Pahwa, Savita; Paradise, C; Day, N. K.; Geha, Raif S.; Schwartz, Stanley A.; Slade, Herbert B.; Oyaizu, Naoki; Good, Robert A.

doi:10.1073/pnas.86.13.5069

Cited by 96 publications

(29 citation statements)

References 39 publications

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“…The phenotype of the Nef-1-expressing cells bears a striking similarity to the phenotypes observed in three recently described cases of severe combined immunodeficiency in human infants (37)(38)(39)(40). In each of these cases, stimulation of the patient's peripheral blood lymphocytes with a variety of external ligands failed to induce IL-2 mRNA, despite being accompanied by the normal IL-2Ra induction and, where examined (37,39), the normal rise in intracellular calcium concentration.…”

Section: Discussionsupporting

confidence: 71%

Expression of the type 1 human immunodeficiency virus Nef protein in T cells prevents antigen receptor-mediated induction of interleukin 2 mRNA.

Luria

Chambers

Berg

1991

Proc. Natl. Acad. Sci. U.S.A.

173

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Stable transformants of the Jurkat T-cell line have been obtained that express either of two distinct forms of the type 1 human immunodeficiency virus nef gene: the nef-1-encoded protein (Nef-1) contains alanine, glycine, and valine at positions 15, 29, and 33, respectively; the protein specified by nef-2 (Nef-2) has threonine, arginine, and alanine at the corresponding positions. When Jurkat cells or their Nef-2-expressing transformants are treated with phorbol 12-myristate 13-acetate (PMA) plus either phytohemagglutinin (PHA) or antibodies against CD3 epsilon, T-cell receptor beta chain, or CD2, there is a prompt increase in interleukin 2 (IL-2) mRNA and intracellular calcium and in the IL-2 receptor alpha chain on the cell surface. Although cells expressing Nef-1 also induce calcium mobilization and the production of IL-2 receptor alpha chain, the formation of IL-2 mRNA is blocked in response to these stimuli. Moreover, Nef-1-expressing cells transfected with a plasmid in which the IL-2 promoter is fused to the chloramphenicol acetyltransferase (CAT) gene fail to induce CAT following treatment with PMA and PHA. By contrast, the parental and Nef-2-containing cells induce CAT normally. Nef-1-expressing cells can produce IL-2 mRNA in response to a combination of PMA and ionomycin, although much less efficiently than the parental Jurkat cells or Nef-2-expressing cells. These findings, and others described herein, suggest that the virally encoded Nef protein interferes with a signal emanating from the T-cell receptor complex that induces IL-2 gene transcription.

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Section: Discussionsupporting

confidence: 71%

Expression of the type 1 human immunodeficiency virus Nef protein in T cells prevents antigen receptor-mediated induction of interleukin 2 mRNA.

Luria

Chambers

Berg

1991

Proc. Natl. Acad. Sci. U.S.A.

173

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“…It has been reported that exogenous application of IL-2 can amplify the proliferation of T lymphocytes in vivo (26). To determine if IL-2 expressed by HSV-IL-2 has biological activity in vivo, we investigated the ability of HSV-IL-2 to increase the lymphoproliferative responses of mice infected with HSV-IL-2 in comparison with the responses of mice infected with parental virus.…”

Section: Structure Of Hsv-il-2mentioning

confidence: 99%

Overexpression of Interleukin-2 by a Recombinant Herpes Simplex Virus Type 1 Attenuates Pathogenicity and Enhances Antiviral Immunity

Ghiasi

Osorio

Perng

et al. 2002

J Virol

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The expression of interleukin-2 (IL-2) has been implicated in the modulation of the outcome of ocular infection with herpes simplex virus type 1 (HSV-1); however, its effects remain controversial. To clarify the role of IL-2, we constructed a recombinant HSV-1 (HSV-IL-2) that expresses two copies of the murine IL-2 gene under the control of the latency-associated transcript (LAT) promoter of HSV-1 in a LAT-negative virus. In tissue culture, the replication of the HSV-IL-2 was 100-fold lower than that of the wild-type virus at a low multiplicity of infection (MOI). Addition of recombinant anti-IL-2 polyclonal antibody markedly enhanced HSV-IL-2 replication in tissue culture. In the 7-day period after ocular infection of BALB/c mice, the replication of HSV-IL-2 was significantly lower than that of wild-type virus in tear cultures, whole eyes, and brain, but was equivalent to wild-type replication in the trigeminal ganglia. Ocular challenge of BALB/c mice with HSV-IL-2 alone, at an MOI that resulted in only 13% survival when parental virus was used, was associated with 90% survival. This decrease in virulence was further shown to be attributable to the expression of IL-2 by coinfection of mice with HSV-IL-2 and the parental virus. This resulted in a decrease in virulence of the parental virus (5% survival when administered alone versus 50% survival on coinfection with HSV-IL-2). The survival of HSV-IL-2-infected mice was compromised by depletion of either IL-2, CD4؉ , or CD8 ؉ T cells (50% survival) and abolished completely by depletion of both T-cell subtypes. Moreover, depletion of CD4 ؉ T cells, CD8 ؉ T cells, or both increased the titers of HSV-IL-2 in the tears, eyes, trigeminal ganglia, and brains of infected mice, so that titers were equivalent to or higher than that of the parental virus. These results suggest that IL-2 expression by recombinant HSV-1 reduces virulence and that depletion of IL-2 or T cells increases virulence in HSV-1-infected mice.

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“…It was therefore not surprising to observe a decreased level of CD3-induced IL-2 secretion in the Syk hi /ZAP-70 Ϫ T cells described here. The importance of IL-2 production in T cell mitogenesis is underscored by the finding that CD3-induced proliferation is severely impaired in murine and human T cells that cannot secrete IL-2 as a result of mutations in the IL-2 gene (35)(36)(37). However, in contrast with these IL-2-deficient cells in which CD3-induced proliferation increases to normal levels in the presence of recombinant IL-2, the profound proliferation defect in CD3-induced Syk hi /ZAP-70 Ϫ T cells could not be alleviated by the addition of exogenous IL-2.…”

Section: Distinct Tcr-induced Responses In Syk Hi /Zap-70 ϫ T Cells 1mentioning

confidence: 99%

Alternative Antigen Receptor (TCR) Signaling in T Cells Derived from ZAP-70-deficient Patients Expressing High Levels of Syk

Noraz¹,

Schwarz²,

Steinberg³

et al. 2000

Journal of Biological Chemistry

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Recombinant interleukin 2 therapy in severe combined immunodeficiency disease.

Cited by 96 publications

References 39 publications

Expression of the type 1 human immunodeficiency virus Nef protein in T cells prevents antigen receptor-mediated induction of interleukin 2 mRNA.

Expression of the type 1 human immunodeficiency virus Nef protein in T cells prevents antigen receptor-mediated induction of interleukin 2 mRNA.

Overexpression of Interleukin-2 by a Recombinant Herpes Simplex Virus Type 1 Attenuates Pathogenicity and Enhances Antiviral Immunity

Alternative Antigen Receptor (TCR) Signaling in T Cells Derived from ZAP-70-deficient Patients Expressing High Levels of Syk

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