Table 1.
Representative approaches for the separation of GVHD and GVL in preclinical models.
| Strategies | Authors,yr | Approaches | Mechanisms | References |
|---|---|---|---|---|
| Cytokines | Teshima et al., 1999 | Interleukin-11 | IL-11 selectively inhibited CD4-mediated GVHD, while retaining both CD4- and CD8-mediated GVL. | (41) |
| Couturier et al., 2013 | IL-22 | The absence of T-cell-derived IL-22 led to a reduction of inflammatory CD8 T cells and an expansion of Treg cells in lymphoid organs as well as a reduction of inflammatory mediators both systemically and in aGVHD target organs, both of which resulted in decreased aGVHD severity without compromising GVL effects. | (59) | |
| Liu et al., 2015 | IL-35 | IL-35 expression leads to the Treg expansion and suppression of Th1 cytokine production, which alleviates aGVHD and retains GVL effects. | (62) | |
| Banovic et al., 2009 | Multipeg-G-CSF | Multipeg–G-CSF could modulate immune function, characterized by the generation of regulatory myelogenous and T cell populations and Th2 differentiation, as well as improve GVL via activation of invariant natural killer (iNK) T cells and enhancement of CTL function. | (24) | |
| Morris et al., 2005 | Potent G-CSF analogs | Mobilization with potent G-CSF analogs thus allowed concurrent enhancement of NKT cell numbers and activities, promoting host DC activation and subsequent CD8-dependent GVL effects while promoting the generation of regulatory T cells to prevent CD4-dependent GVHD. | (19) | |
| Depletion of alloreactive cells | Zheng et al., 2008 | Naïve CD4+ T cells | TEMs did not induce high systemic levels of TNF-α and IFN-γ in recipients, as did TNs. In ddition, a greater fraction of TNs produced IFN-γ. GVL mediated by CD4+ TNs was intact even when both perforin- and FasL-mediated killing were prevented. | (63, 64) |
| Adoptive transfer of immune cells | Ghosh et al., 2017 | CAR-T cells | Allogeneic donor CD19-specific CD28z CAR T cells promote anti-lymphoma activity, with minimal GVHD. | (40) |
| Song et al., 2018 | NK cells | IL-12/15/18-preactivated NK cells predominantly mediated the lysis of donor allo-reactive T cells to inhibit aGVHD without promising GVL effects. | (20) | |
| Regulatory immune cells | Sato et al., 2003 | Regulatory DCs | Allogeneic regulatory DC regulation of the cytotoxic activity of transplanted CD8+ T cells, which failed to cause acute GVHD, might be sufficient to cause an efficient GVL effect. | (61) |
| Heinrichs et al., 2016 | Tregs | Harnessing the unique differences between alloreactive CD4+ and CD8+ iTregs could create an optimal iTreg therapy for GVHD prevention with maintained GVL responses. | (57) | |
| Li et al., 2014 | MSCs | Directing the migration of MSCs by CCR7 from their broad battle field (inflammatory organs) to the modulatory center (SLOs) of immune response could attenuate GvHD while preserving the GvL effect. | (25, 27) | |
| Highfill et al., 2010 | MDSCs | MDSCs generated in the presence of IL-13 could inhibit GVHD, migrate to sites of allopriming, and limit the activation and proliferation of donor T cells, but they did not diminish the GVL effect of donor T cells. | (53) | |
| Darlak et al., 2013 | pDCs | Enrichment of pDCs might augment GVL without increasing GVHD is through the production of IFN-α and/or IL-13 by pDCs. | (60) | |
| Signaling pathway | Vaeth et al., 2015 | Nuclear factor of activated T cells | Ablation of NFAT1, NFAT2, or a combination of both resulted in ameliorated GVHD due to reduced proliferation, target tissue homing, and impaired effector function of allogenic donor T cells. In addition, the beneficial antitumor activities were largely preserved in NFAT-deficient effector T cells. | (65) |
| Haarberg et al., 2013 | Inhibition of PKCα and PKCθ | Inhibition of PKCα and PKCθ impaired donor T-cell proliferation, migration, and chemokine/cytokine production and significantly decreased GVHD, but spared T-cell cytotoxic function and GVL effects. | (66) | |
| Schutt et al., 2018 | Inhibition of the IRE-1α/XBP-1 pathway | Inhibition of the IRE-1a/XBP-1 pathway regulated B-cell activation and function and prevented the development of cGVHD while preserving GVL. | (67) | |
| Itamura et al., 2016 | RAS/MEK/ERK pathway | MEK inhibitors affected human T cells in a memory stage-dependent manner, i.e., they selectively inhibited naive and central memory T cells while sparing effector memory T cells. | (68) | |
| Pharmacological agents | Sun et al., 2004 | Proteasome inhibitor | Bortezomib might rapidly induce the preferential deletion of the very high-affinity alloreactive T cells, thus allowing expansion of the remaining T cells that maintain GVT responses yet have a reduced potential for promoting GVHD. | (38) |
| Strokes et al., 2016 | Bendamustine | BEN alleviated GVHD via enhancing MDSC suppressive function without promising GVL effects. | (69) | |
| Choi et al., 2010 | Azacitidine | AzaC could mitigate GVHD while preserving GVL by peripheral conversion of alloreactive effector T cells into FOXP3+ Tregs and epigenetic modulation of genes downstream of Foxp3 required for the suppressor function of Tregs. | (70) | |
| Ehx et al., 2017 | Azacitidine | AZA significantly decreased human T-cell proliferation as well as IFN-γ and TNF-α serum levels, and it reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells, leading to prevention of GVHD without compromising GVL effects. | (71) | |
| Others | Ghosh et al., 2013 | Promyelocytic leukemia zinc finger | PLZF-TG T cells mediated less GVHD due to Fas-mediated fratricidal regulation and the biphenotypic TH1/TH2 response leading to limited alloreactive expansion, and an intact GVT activity. | (72) |
| Marcondes et al., 2014 | a-1-antitrypsin | Treatment of transplant donors with human AAT resulted in an increase in IL-10 messenger RNA and CD8+CD11c+CD205+MHC II+DCs, and the prevention or attenuation of acute GVHD in the recipients. The GVL effect was maintained or even enhanced with AAT treatment of the donor, mediated by an expanded population of NK1.1+, CD49B+, CD122+, and CD335+ NKG2D-expressing NK cells. | (35) | |
| Wu et al., 2015 | MicroRNA-17-92 | Blockade of miR-17 or miR-19b in this cluster significantly inhibited alloreactive T-cell expansion and IFN-γ production, and it prolonged survival in recipients afflicted with GVHD while preserving the GVL effect. | (73) |
GVL, graft-versus-leukemia; GVHD, graft-versus-host disease; Tregs, regulatory T cells; aGVHD, acute GVHD; G-CSF, granulocyte colony-stimulating factor; DCs, dendritic cells; TEM, effector memory T cell; TN, naïve T cells; IFN-γ, interferon-γ; CAR-T, chimeric antigen receptor T; MSCs, mesenchymal stem cells; MDSCs, myeloid-derived suppressive cells; pDCs, plasmoid dendritic cells; TNF-α, tumor necrosis factor-α