Pretreatment with Anti-CD3 Monoclonal Antibody Depletes Recipient CCR7⁺ Dendritic Cells and Prevents Graft-Versus-Host Disease While Preserving GVL Effects,

Abstract 4024

Administration of anti-CD3 after allogeneic hematopoietic cell transplantation (HCT) has been applied in humans to directly prevent alloreactive donor T cell activation/expansion and prevent as well as treat graft versus host disease (GVHD), but the results are discouraging. We recently reported that anti-CD3 treatment of recipients before allogeneic HCT prevented GVHD and preserved strong GVL effects in mice, but the mechanisms remained unclear. Moreover, the applicability of this approach in humans is limited by cytokine storm syndrome induced by FcR-binding anti-CD3 mAb. In the current studies, we observed that treatment with anti-CD3 seven days before HCT did not reduce donor T cell activation/expansion but markedly reduced donor T expression of tissue-specific homing and chemokine receptors (i.e. gut homing α4β7 and CCR9 or skin homing E-ligand, P-ligand,CCR4, and CCR10) and prevented donor T migration into GVHD target tissues. Furthermore, recipient CCR7⁺ dendritic cells in the mesenteric and peripheral lymph nodes were required to induce donor T expression of tissue-specific homing and chemokine receptors. Anti-CD3 treatment before HCT depleted the host CCR7⁺ DCs in lymph nodes via induction of apoptosis. Thus, activated donor T cells were confined to lympho-hematopoietic tissues in the recipient where they could mediate GVL effects, but they could not migrate into recipient epithelial tissues where they would otherwise cause GVHD. Reinfusion of DCs from PBS-treated recipients into anti-CD3-treated recipients restored the presence of CCR7⁺ DCs in the lymph nodes, induced donor T expression of homing and chemokine receptors, and induced GVHD. These results demonstrate that depletion of host CCR7⁺ DCs in lymph nodes after anti-CD3 treatment plays an important role in preventing GVHD while preserving GVL effects. Additionally, injection of FcR-non-binding anti-CD3 IgG3 before treatment with FcR-binding anti-CD3 prevented cytokine storm syndrome without reducing the effectiveness of GVHD prevention. We propose that similar treatment of recipients with anti-CD3 mAb could be used to prevent GVHD in humans.