TY - JOUR
T1 - In vitro engagement of CD3 and CD28 corrects T cell defects in chronic lymphocytic leukemia
AU - Bonyhadi, Mark
AU - Frohlich, Mark
AU - Rasmussen, Angela
AU - Ferrand, Christophe
AU - Grosmaire, Laura
AU - Robinet, Eric
AU - Leis, Jose
AU - Maziarz, Richard T.
AU - Tiberghien, Pierre
AU - Berenson, Ronald J.
PY - 2005/2/15
Y1 - 2005/2/15
N2 - Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of leukemic B cells concomitant with immunological abnormalities and depressed immune responses. The T cell abnormalities found in CLL patients are thought to increase the risk of infection and hamper immune recognition and elimination of leukemic cells. We evaluated whether providing signals through CD3 and CD28 would correct some of these T cell defects. PBMC were incubated with anti-CD3 and anti-CD28 mAbs conjugated to superparamagnetic beads for 12-14 days. This resulted in a 1400-fold increase in T cell numbers. Activated T cells expressed high levels of CD25, CD54, CD137, and CD154, and produced IFN-γ, TNF-α, and GM-CSF. The mean T cell composition of cultures increased from ∼6% to >90% and leukemic B cells decreased from a mean of ∼85% to 0.1% or less. Leukemic B cells up-regulated expression of CD54, CD80, CD86, and CD95. Receptor up-regulation required direct cell contact with the activated T cells and could be blocked with anti-CD154 mAb, suggesting that the CD40-CD40L pathway helped mediate these effects. Poor T cell responses to allostimulation were corrected by the activation and expansion process. The skewing in the TCR repertoire returned to normal, or near normal following the culture process in eight of nine patients with abnormal TCR repertoires. Activated T cells had potent in vitro antileukemic effects in contrast to nonactivated T cells. Based upon these findings, a clinical trial has been initiated to test the potential therapeutic effects of T cells activated using this approach in patients with CLL.
AB - Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of leukemic B cells concomitant with immunological abnormalities and depressed immune responses. The T cell abnormalities found in CLL patients are thought to increase the risk of infection and hamper immune recognition and elimination of leukemic cells. We evaluated whether providing signals through CD3 and CD28 would correct some of these T cell defects. PBMC were incubated with anti-CD3 and anti-CD28 mAbs conjugated to superparamagnetic beads for 12-14 days. This resulted in a 1400-fold increase in T cell numbers. Activated T cells expressed high levels of CD25, CD54, CD137, and CD154, and produced IFN-γ, TNF-α, and GM-CSF. The mean T cell composition of cultures increased from ∼6% to >90% and leukemic B cells decreased from a mean of ∼85% to 0.1% or less. Leukemic B cells up-regulated expression of CD54, CD80, CD86, and CD95. Receptor up-regulation required direct cell contact with the activated T cells and could be blocked with anti-CD154 mAb, suggesting that the CD40-CD40L pathway helped mediate these effects. Poor T cell responses to allostimulation were corrected by the activation and expansion process. The skewing in the TCR repertoire returned to normal, or near normal following the culture process in eight of nine patients with abnormal TCR repertoires. Activated T cells had potent in vitro antileukemic effects in contrast to nonactivated T cells. Based upon these findings, a clinical trial has been initiated to test the potential therapeutic effects of T cells activated using this approach in patients with CLL.
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U2 - 10.4049/jimmunol.174.4.2366
DO - 10.4049/jimmunol.174.4.2366
M3 - Article
C2 - 15699173
AN - SCOPUS:13544256621
SN - 0022-1767
VL - 174
SP - 2366
EP - 2375
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -