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Title: Optimization of in vitro expansion of macaque CD4<sup>+</sup>T cells using anti-CD3 and co-stimulation for autotransfusion therapy
Authors: Nattawat Onlamoon
Krystal Hudson
Patsy Bryan
Ann E. Mayne
Mark Bonyhadi
Ron Berenson
Bruce J. Sundstrom
Pavel Bostik
Aftab A. Ansari
François Villinger
Emory University School of Medicine
Mahidol University
Cyclacel Pharmaceuticals, Inc.
Keywords: Agricultural and Biological Sciences;Veterinary
Issue Date: 1-Aug-2006
Citation: Journal of Medical Primatology. Vol.35, No.4-5 (2006), 178-193
Abstract: Background: Our laboratory has previously shown that adoptive transfer of in vitro-expanded autologous purified polyclonal CD4+T cells using anti-CD3/CD28-coated beads induced antiviral responses capable of controlling SIV replication in vivo . Methods: As CD4+T cells comprise several phenotypic and functional lineages, studies were carried out to optimize the in vitro culture conditions for maximal CD4+T-cell expansion, survival and delineate the phenotype of these expanded CD4+T cells to be linked to maximal clinical benefit. Results and Conclusions: The results showed that whereas anti-monkey CD3γ/ε was able to induce T-cell proliferation and expansion in combination with antibodies against multiple co-stimulatory molecules, monkey CD3ε cross reacting antibodies failed to induce proliferation of macaque CD4+T cells. Among co-stimulatory signals, anti-CD28 stimulation was consistently superior to anti-4-1BB, CD27 or ICOS while the use of anti-CD154 failed to deliver a detectable proliferation signal. Increasing the relative anti-CD28 co-stimulatory signal relative to anti-CD3 provided a modest enhancement of expansion. Additional strategies for optimization included attempts to neutralize free radicals, enhancement of glucose uptake by T cells or addition of T-cell stimulatory cytokines. However, none of these strategies provided any detectable proliferative advantage. Addition of 10 autologous irradiated feeder cells/expanding T cell provided some enhancement of expansion; however, given the high numbers of T cell needed, this approach was deemed impractical and costly, and lower ratios of feeder to expanding T cells failed to provide such benefit. The most critical parameter for efficient expansion of purified CD4+T cells from multiple monkeys was the optimization of space and culture conditions at culture inception. Finally, anti-CD3/28-expanded CD4+T cells uniformly exhibited a central memory phenotype, absence of CCR5 expression, marked CXCR4 expression in vitro , low levels of caspase 3 but also of Bcl-2 expression. © 2006 The Authors Journal compilation 2006 Blackwell Munksgaard.
ISSN: 16000684
Appears in Collections:Scopus 2006-2010

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