Anti-CD3 preconditioning separates GVL from GVHD via modulating host dendritic cell and donor T-cell migration in recipients conditioned with TBI

Abstract

Host dendritic cells (DCs) play a critical role in initiating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL), and separation of GVL from GVHD remains a major challenge in the treatment of hematologic malignancies by allogeneic hematopoietic cell transplantation (HCT). Here, we show that preconditioning with anti-CD3 monoclonal antibody before conditioning with total body irradiation (TBI) prevents GVHD but retains GVL in a HCT model of major histocompatibility complex (MHC)-mismatched C57BL/6 donor to BALB/c host. Prevention of GVHD is associated with inhibition of donor T-cell expression of homing and chemokine receptors, and inhibition of GVHD target tissue expression of chemokines. Furthermore, inhibition of donor T-cell expression of gut homing ␣4␤7 and chemokine receptor (CCR)9 by anti-CD3 preconditioning results from a reduction of CD103 ؉ DCs in draining mesenteric lymph nodes (LNs), which is associated with down-regulation of DC expression of CCR7, a receptor IntroductionIn allogeneic hematopoietic cell transplantation (HCT), both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) activity are predominantly mediated by donor T cells in bone marrow grafts. 1-4 Donor T cells are activated in host lymphoid tissues and then migrate to epithelial GVHD target tissues (ie, gut, liver, lung, and skin) to mediate GVHD. [5][6][7] Studies have shown that inhibition of donor T-cell migration to GVHD target tissues prevents GVHD but retains GVL activities in lymphohematologic tissues. 8,9 Alloreactive T cells are activated by host antigen-presenting cells (APCs), especially dendritic cells (DCs), in secondary lymphoid tissues. 10,11 It has been proposed that, during activation, host DCs in draining lymph nodes (LNs) induce donor T cells to express homing and chemokine receptors (CCRs) that medicate tissuespecific migration. 12 It has been shown that DCs in mesenteric LNs (MLNs) induce T-cell expression of ␣4␤7 receptors and CCR9 that mediate T-cell migration to gut tissues, 13,14 because DCs in MLNs are able to metabolize vitamin A into retinoic acid (RA) that induces T cells to up-regulate ␣4␤7 and CCR9. 15 Similarly, DCs in peripheral LNs induce T-cell expression of E-selectin ligand (E-Lig), P-selectin ligand (P-Lig), CCR4, and CCR10 that mediate T-cell migration to skin tissue, 14,16,17 because DCs in peripheral LNs are able to metabolize vitamin D3 to an active form that induces T cells to up-regulate CCR10 18 T-cell expression of chemokine receptors as well as GVHD target tissue release of chemokines has been shown to play critical roles in the control of donor T-cell migration to GVHD target tissues. [19][20][21][22][23][24][25][26] It has been proposed that CD103 ϩ DCs in lamina propria (LP) capture antigens locally and then migrate via afferent lymph to draining MLN, where they activate naive T cells and induce expression of gut tissue-specific homing and chemokine receptors. 27 It has also been indicated that DC migration from LP to MLN and from dermis to peripheral LN (PLN)...

Anti-CD3 Antibody Ameliorates Transfusion-Associated Graft-Versus-Host Disease in a Chemotherapy-Based Mouse Model With Busulfan and Fludarabine

“…Still, some other mechanisms might also play a role. Anti-CD3 can regulate the expression of chemokine receptors, as well as target organ protective molecules, such as B7H1 and indoleamine 2,3-dioxygenase (9,13) . Further research is necessary to determine the mechanisms underlying the improvement of TA-GVHD.…”

“…In clinical practice, large doses of glucocorticoids and immune inhibitors (such as CsA and CTX) were used to treat TA-GVHD. Recently, anti-CD3-based conditioning regimen was reported to separate GVL from GVHD in animal models (13) . Subsequently, we tested these treatments.…”

“…Mitogenic anti-CD3 can cause cytokine storm (14) . To avoid such side effects and determine the safe dose to treat TA-GVHD, we titrated down the dose from 5 mg/kg as described in animal models (13) . Serum concentrations of cytokines (IL-2, IL-6, TNF-α, and IFN-γ) were measured at 0.5, 1, 4, and 24 h after treatments.…”

Induction of Mixed Chimerism Depletes Pre-existing and De Novo–Developed Autoreactive B Cells in Autoimmune NOD Mice

“…Antibodies for CD24(30-F1), CD4(GK1.5), IgM(II/41) IgD (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), BP1(6C3), CD19(eBio1D3), CD43(eBioR2/60), and CD23(B3B4) as well as efluor 450-labeled streptavidin were purchased from eBioscience (San Diego, CA). Dead cells were excluded using DAPI or aqua fluorescent reactive dye (Invitrogen, Carlsbad, CA).…”

“…We have demonstrated that induction of mixed chimerism via hematopoietic cell transplantation (HCT) is an effective therapy to reverse autoimmune T1D in NOD mice, using a radiation-free nontoxic anti-CD3/CD8 conditioning regimen (19)(20)(21)(22)(23)(24)(25)(26). Induction of chimerism…”