Defects in T-cell–mediated immunity to influenza virus in murine Wiskott-Aldrich syndrome are corrected by oncoretroviral vector–mediated gene transfer into repopulating hematopoietic cells

Abstract

IntroductionThe Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease of quite variable expressivity, classically described as a triad of immunodeficiency, thrombocytopenia, and eczema. 1,2 Opportunistic infection, hemorrhage, or malignancies are the most frequent causes of death of affected males, who rarely survive beyond the age of 20 years. 3 Hematopoietic stem cell transplantation may be curative, but most patients lack a suitable related or unrelated matched donor, and transplantation after the age of 5 years is associated with a poor outcome. 4 Thus, alternative therapeutic approaches are needed.The gene affected by mutations in patients with WAS encodes a 54-kilodalton (kDa) polypeptide termed the WAS protein (WASP), which is expressed exclusively in hematopoietic cells. 5 Functional studies suggests that WASP transmits and integrates signals arising at the cell membrane that result in shape changes or cell movement through reorganization of the actin cytoskeleton. 5,6 Although defects in B-cell, macrophage, and dendritic cell function have been demonstrated, 6-8 T-cell dysfunction is thought to be central to the immunodeficiency exhibited by patients with WAS. T-cell lines derived from patients with WAS exhibit impaired mitogenesis and cytokine secretion after T-cell-receptor stimulation. 5 We 9 and others 10,11 have recently shown that these defects, which are also exhibited by primary T cells, can be corrected by oncoretroviral vector-mediated transfer of the WAS gene into T cells obtained from patients and expanded ex vivo. These results suggest that wild type (WT) or gene-corrected T cells may have a competitive repopulating advantage over WASP Ϫ T cells in vivo, a feature that would make gene therapy for WAS more likely to succeed.Two mouse strains having WASP deficiency have been created by gene knockout technology. 12,13 Hemizygous deficient male (WASP Ϫ ) animals of both strains exhibit T-cell functional deficiencies analogous to those observed in patients with WAS, namely, poor T-cell proliferation and cytokine secretion in response to T-cell-receptor stimulation and also moderate lymphopenia and thrombocytopenia, which can be normalized by transplantation. 14 The availability of a mouse model of WAS now allows the evaluation of gene therapy approaches for correction of the critical defects in hematopoietic lineages caused by deficiency of WASP. Oncoretroviral vector-mediated gene transfer has been used successfully to evaluate gene therapy strategies in several murine models of human immunodeficiencies including those caused by deficiency of the common ␥-chain expressed in T-cell cytokine receptors, 15,16 Jak3 kinase deficiency, 17 deficiency in the zap70 protein, 18 and RAG-2 deficiency. 19 In human trials, gene therapy has resulted in clinical improvement in patients with deficiencies in the receptor common ␥-chain 20 or adenosine deaminase. 21 In the present study, we determined the relative ability of bone marrow cells from WT versus WAS animals to repopulate various hematopoieti...

Defective Th1 Cytokine Gene Transcription in CD4+ and CD8+ T Cells from Wiskott-Aldrich Syndrome Patients

“…ϩ T cells and defective cytokine production have been previously reported in WASP knockout mice, in which the clearance of influenza A virus upon primary infection was normal, but the secondary response was impaired (29,39). In response to TCR/CD28-driven stimulation, WAS CD4 ϩ T cells display impaired production of Th1 cytokines (IL-2, IFN-␥, and TNF-␣), while the production of Th2 cytokines (IL-4, IL-10, and IL-5) is minimally affected.…”

Stem cell transplantation for the Wiskott–Aldrich syndrome: a single-center experience confirms efficacy of matched unrelated donor transplantation

“…This may also impact on future therapeutic strategies for WAS such as gene therapy. A number of investigators have pursued gene replacement as an alternative strategy for WAS using mouse models [20][21][22][23][24] or by transducing human T cells. [25][26][27] However, given that the animal model fails to fully recapitulate the platelet defects seen in humans, 28 the direct relevance of these approaches to correction of human WAS…”

Wiskott-Aldrich syndrome protein–mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells

“…A similar inability of pDCs to make type-I IFN in response to a secondary challenge has already been described in the context of viral infections (Björck, 2004;Ito et al, 2006), in lupus-prone mice (Pau et al, 2012), and in SLE patients (Kwok et al, 2008a). Whether exhaustion of the IFN- pathway is playing a role in inefficient viral clearance in WKO mice (Strom et al, 2003;Andreansky et al, 2005) will be a subject of future studies and it is certainly an important implication of our findings. Second and most compelling, we demonstrated with different approaches that WASp-deficient pDCs are inherently hyperresponsive to TLR9 triggering.…”