The humanized anti-HLA-DR moAb, IMMU-114, depletes APCs and reduces alloreactive T cells: implications for preventing GVHD.
In contrast to the conventional immunosuppressive agents and nonselective T-cell-depleting antibodies, selective depletion of donor alloreactive T cells and/or host APCs, particularly DCs, represents a novel approach that can effectively control GVHD with less or no impairment of T-cell-mediated antiviral and GVL immunity. Here we report that IMMU-114, a humanized anti-human leukocyte antigen-DR (HLA-DR) moAb, efficiently depleted human PBMCs of all APCs, including B cells, monocytes, myeloid DC type-1 (mDC1), mDC2 and plasmacytoid DCs (pDCs). Early and late apoptosis of mDC1, mDC2 and pDCs, and late apoptosis of all APC subsets, were increased by IMMU-114 treatment. Although IMMU-114 had little, if any, effect on the survival and apoptosis of non-B lymphocytes (>80% of which are T cells and ∼1-2% of T cells express HLA-DR), it selectively inhibited the proliferation of purified HLA-DR(+) T cells rather than HLA-DR(-) T cells. As a consequence, IMMU-114 treatment resulted in suppressed T-cell proliferation and reduced CD25(+) alloreactive T cells in allogeneic MLRs. Given the critical roles of APCs and alloreactive T cells in the pathogenesis of GVHD, these results suggest that IMMU-114 may have therapeutic potential against GVHD.
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Morris Plains, NJ 07950, USA. mchen@gscancer.org
X
X
Chen
C-H
CH
Chang
R
R
Stein
D M
DM
Goldenberg
D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control*; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D061067:Antibodies, Monoclonal, Humanized; D006684:HLA-DR Antigens; C577236:IMMU-114