Anti‐CD3/28 mediated expansion of macaque CD4<sup>+</sup> T cells is polyclonal and provides extended survival after adoptive transfer

Onlamoon, Nattawat; Plagman, N.; Rogers, Kenneth A.; Mayne, Ann E.; Boštík, Pavel; Pattanapanyasat, Kovit; Ansari, Aftab A.; Villinger, François

doi:10.1111/j.1600-0684.2007.00238.x

Cited by 15 publications

(17 citation statements)

References 66 publications

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“…We initially used concanavalin A (Con A) for the stimulation of CD4+ T cells (CD4T-1), but Con A only induced a 12-fold cell expansion after 7 days. In order to improve the ex vivo expansion, we used anti-CD3/anti-CD28 monoclonal antibody-conjugated beads (anti-CD3/CD28 beads), which are known to yield a more efficient cellular expansion [7], [8]. As we expected, the fold expansion of CD4+ T cells (CD4T-2 and CD4T-3) stimulated with anti-CD3/CD28 beads was much higher than with Con A stimulation (Table 1).…”

Section: Resultsmentioning

confidence: 88%

In Vivo Safety and Persistence of Endoribonuclease Gene-Transduced CD4+ T Cells in Cynomolgus Macaques for HIV-1 Gene Therapy Model

et al. 2011

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BackgroundMazF is an endoribonuclease encoded by Escherichia coli that specifically cleaves the ACA sequence of mRNA. In our previous report, conditional expression of MazF in the HIV-1 LTR rendered CD4+ T lymphocytes resistant to HIV-1 replication. In this study, we examined the in vivo safety and persistence of MazF-transduced cynomolgus macaque CD4+ T cells infused into autologous monkeys.Methodology/Principal FindingsThe in vivo persistence of the gene-modified CD4+ T cells in the peripheral blood was monitored for more than half a year using quantitative real-time PCR and flow cytometry, followed by experimental autopsy in order to examine the safety and distribution pattern of the infused cells in several organs. Although the levels of the MazF-transduced CD4+ T cells gradually decreased in the peripheral blood, they were clearly detected throughout the experimental period. Moreover, the infused cells were detected in the distal lymphoid tissues, such as several lymph nodes and the spleen. Histopathological analyses of tissues revealed that there were no lesions related to the infused gene modified cells. Antibodies against MazF were not detected. These data suggest the safety and the low immunogenicity of MazF-transduced CD4+ T cells. Finally, gene modified cells harvested from the monkey more than half a year post-infusion suppressed the replication of SHIV 89.6P.Conclusions/SignificanceThe long-term persistence, safety and continuous HIV replication resistance of the mazF gene-modified CD4+ T cells in the non-human primate model suggests that autologous transplantation of mazF gene-modified cells is an attractive strategy for HIV gene therapy.

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Section: Resultsmentioning

confidence: 88%

In Vivo Safety and Persistence of Endoribonuclease Gene-Transduced CD4+ T Cells in Cynomolgus Macaques for HIV-1 Gene Therapy Model

et al. 2011

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“…As a proof of concept for future clinical adoptive therapy studies, we attempted to disrupt the ccr5 and cxcr4 genes with ZFNs in rhesus macaque CD4+ T cells. Briefly, rhesus CD4+ T cells were isolated from whole blood, purified by magnetic bead negative selection, and then stimulated with anti-CD3/anti-CD28 coated beads as previously described [35], [36]. As the 24 bp X4-ZFPs' binding site is identical between rhesus and humans, we were able to utilize the same ZFN pair.…”

Section: Resultsmentioning

confidence: 99%

“…CD4+ T cells were then isolated by negative selection with a non-human primate CD4+ T cell selection kit (Miltenyi). Cells were then stimulated with 1∶4 anti-CD3 (clone FN-18)/anti-CD28 (clone L293) M-450 tosylactivated beads (Invitrogen) at a ratio of 1 bead per cell [35], [36].…”

Section: Methodsmentioning

confidence: 99%

Engineering HIV-Resistant Human CD4+ T Cells with CXCR4-Specific Zinc-Finger Nucleases

et al. 2011

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HIV-1 entry requires the cell surface expression of CD4 and either the CCR5 or CXCR4 coreceptors on host cells. Individuals homozygous for the ccr5Δ32 polymorphism do not express CCR5 and are protected from infection by CCR5-tropic (R5) virus strains. As an approach to inactivating CCR5, we introduced CCR5-specific zinc-finger nucleases into human CD4+ T cells prior to adoptive transfer, but the need to protect cells from virus strains that use CXCR4 (X4) in place of or in addition to CCR5 (R5X4) remains. Here we describe engineering a pair of zinc finger nucleases that, when introduced into human T cells, efficiently disrupt cxcr4 by cleavage and error-prone non-homologous DNA end-joining. The resulting cells proliferated normally and were resistant to infection by X4-tropic HIV-1 strains. CXCR4 could also be inactivated in ccr5Δ32 CD4+ T cells, and we show that such cells were resistant to all strains of HIV-1 tested. Loss of CXCR4 also provided protection from X4 HIV-1 in a humanized mouse model, though this protection was lost over time due to the emergence of R5-tropic viral mutants. These data suggest that CXCR4-specific ZFNs may prove useful in establishing resistance to CXCR4-tropic HIV for autologous transplant in HIV-infected individuals.

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“…The animal was assigned to a research protocol that studied immune restoration via transfusions of autologous in vitro expanded CD4 + T cells to SIV‐infected macaques . The subject was intravenously infected with SIVmac239.…”

Section: Methodsmentioning

confidence: 99%

PAS‐positive extracellular deposits within germinal centers of hyperplastic follicles during SIV infection in a rhesus macaque

Hong¹,

Villinger

Courtney

2014

J of Medical Primatology

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Background Lymphoid tissue remodeling is characteristic of chronic SIV infection. Methods A rhesus macaque infected with SIVmac239 was necropsied and its lymphoid tissues subjected to histopathology characterization. Results Germinal centers in spleen and lymph nodes contained PAS-positive, non-amyloid extracellular deposits, decreased T follicular helper cells, and normal density of Ki67+ B cells. Conclusions A possible mechanism for PAS-positive deposits includes exaggerated involution of SIV-induced follicular hyperplasia secondary to virus-associated immune reaction.

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Anti‐CD3/28 mediated expansion of macaque CD4⁺ T cells is polyclonal and provides extended survival after adoptive transfer

Abstract: In summary, the data suggest that anti-CD3/28 mediated expansion of CD4(+) T cells retains its immunotherapeutic potential not only during the early stages of lentiviral infection but also at more advanced stages of disease.

Cited by 15 publications

References 66 publications

In Vivo Safety and Persistence of Endoribonuclease Gene-Transduced CD4+ T Cells in Cynomolgus Macaques for HIV-1 Gene Therapy Model

In Vivo Safety and Persistence of Endoribonuclease Gene-Transduced CD4+ T Cells in Cynomolgus Macaques for HIV-1 Gene Therapy Model

Engineering HIV-Resistant Human CD4+ T Cells with CXCR4-Specific Zinc-Finger Nucleases

PAS‐positive extracellular deposits within germinal centers of hyperplastic follicles during SIV infection in a rhesus macaque

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Anti‐CD3/28 mediated expansion of macaque CD4+ T cells is polyclonal and provides extended survival after adoptive transfer

Abstract: In summary, the data suggest that anti-CD3/28 mediated expansion of CD4(+) T cells retains its immunotherapeutic potential not only during the early stages of lentiviral infection but also at more advanced stages of disease.

Cited by 15 publications

References 66 publications

In Vivo Safety and Persistence of Endoribonuclease Gene-Transduced CD4+ T Cells in Cynomolgus Macaques for HIV-1 Gene Therapy Model

In Vivo Safety and Persistence of Endoribonuclease Gene-Transduced CD4+ T Cells in Cynomolgus Macaques for HIV-1 Gene Therapy Model

Engineering HIV-Resistant Human CD4+ T Cells with CXCR4-Specific Zinc-Finger Nucleases

PAS‐positive extracellular deposits within germinal centers of hyperplastic follicles during SIV infection in a rhesus macaque

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Anti‐CD3/28 mediated expansion of macaque CD4⁺ T cells is polyclonal and provides extended survival after adoptive transfer