Cell-type-specific cytotoxicity of anti-CD4 and anti-CD8 ricin immunotoxins
against human alloreactive T-cell clones
FM Uckun, DE Myers, JA Ledbetter, SL Wee and DA Vallera
Tumor Immunology Laboratory, University of Minnesota Health Sciences
Center, Minneapolis.
Potent T-cell subset-directed immunotoxins (ITs) were generated by
conjugating the anti-CD4 monoclonal antibody (MoAb) G17-2 and the anti- CD8
MoAb G10.1 to the ribosome-inhibitory protein, ricin. The cell-type-
specific cytotoxicities of the generated ITs were evaluated at the clonal
level using human alloreactive T-cell clones. The kinetics of anti-CD4
ricin-induced inactivation of protein synthesis in target CD4+ cloned
T-cells was first order with no detectable lag period and a maximum rate of
0.07 logs per hour (t10 = 13.6 hours; first-order rate constant/K = 0.17
hr-1). The alloantigen specific lytic function of the CD4+ cytolytic T-cell
clone JMAC28 was acutely sensitive to anti-CD4 ricin, and no residual lytic
activity against allogeneic targets was detectable 24 hours after treatment
with as little as 0.5 mmol/L anti- CD4 ricin. Notably, both anti-CD4 ricin
and anti-CD8 ricin elicited a selective and dose-dependent inhibition of
clonal proliferation of target T-cell clones with a maximum kill of greater
than 3 logs at 5 nmol/L. No significant "bystander effects" were observed
for non-target cells. Bone marrow progenitor cells CFU-GM, BFU-E, and
CFU-GEMM were only minimally affected by either IT. We conclude that these
ITs show considerable potential for effective depletion of T-cell
subpopulations from allogeneic donor marrow grafts for clinical
graft-versus-host disease (GVHD) prophylaxis.
Volume 74,
Issue 7,
pp. 2445-2454,
11/15/1989
Copyright © 1989 by The American Society of Hematology
