Alefacept selectively promotes NK cell‐mediated deletion of CD45R0⁺ human T cells

Abstract

Modulation of the immune response using immunoglobulin fusion proteins has shown great promise for clinical immunotherapy of autoimmune diseases. Alefacept is an immunoglobulin fusion protein composed of the first extracellular domain of human LFA-3 fused to the hinge, C H 2 and C H 3 domains of human IgG 1 . Alefacept has previously been reported to inhibit T cell proliferation. Here, we analyzed the effects of alefacept on lymphocytes in vitro and characterized the role of autologous NK cells in its mechanism of action. Alefacept, but not a C H 2 binding mutant of Alefacept, inhibited CD3-induced T cell proliferation only in the presence of live NK cells, consistent with an important role for Fc + R engagement. Alefacept caused preferential depletion of CD69+ T cell subsets. Cytotoxicity assays revealed that alefacept, but not the C H 2 binding mutant, induced NK cell-mediated death of activated T cells and sorting into CD45R0 + and CD45RA + subpopulations showed that lymphocyte deletion occurred preferentially in the CD45R0 + subset. Activated CD45R0 + cells expressed higher levels of CD2 than CD45R0 -cells, providing a possible explanation for the selective targeting of this subset. Our results suggest that selective targeting of CD45R0 + T cells by NK cells represents a potential therapeutic mechanism of action of alefacept.

Rapid response to alefacept given to patients with steroid resistant or steroid dependent acute graft-versus-host disease: a preliminary report

“…We speculate that this effect may be due in part to direct blockage of CD2 and LFA-3 on the one hand, and to the increased allogeneic NK cell activity 22 that in conjunction with the Fc end of the alefacept may induce cytotoxicity of alloreactive T cells, thus downregulating GVHD activity. 17 Another possible theory to explain the rapid response against infiltrating T cells involved in GVHD may be related to neutralization of activated Fc positive dendritic cells and inflammatory genes as shown in psoriasis 23 especially combined with the other immunosuppressive agents given for GVHD.…”

Alefacept treatment for refractory chronic extensive GVHD

“…Again, we hypothesize that the effect of alefacept on GVHD is augmented by the increased allogeneic NK-cell activity, 29 which in conjunction with the Fc end of the alefacept may induce cytotoxicity of alloreactive T cells, thus downregulating GVHD activity. We conclude that on the basis of our limited experience, alefacept is a promising agent for clinical application for treatment patients with extensive cGVHD even when refractory.…”

Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir?

“…The role of macrophages/ monocyte in ADCP and their FcγR has been comprehensively reviewed by Gorgon et al [84]. Studies with human purified T cells and NK cells from human peripheral blood in culture [6,11] or mixed lymphocyte reaction assay on human PBMC that are devoid of neutrophils showed FcγRI and FcγRIII but not FcγRII involved in NK cell-mediated ADCC. However, studies using transgenic mice expressing human CD2 confirmed depletion of T cells in vivo but NK cell depletion via anti-asialo GMl pretreatment did not inhibit alefacept-mediated T cell depletion in these mice.…”

“…Alefacept is effective for psoriasis and other T cell-mediated autoimmune diseases [5,[10][11][12][13][14][15][16][17][18]. Alefacept responses are noteworthy for their durability.…”