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S. Copsel et al.
tously expressed. TNF-a, the natural ligand, is a pleiotrop- ic cytokine with dual function (pro- and anti-inflammato- ry) which exists in both membrane-bound and soluble forms. Membrane bound TNF-a preferentially interacts with TNFR2 and results in a suppressive function due to the lack of a cytoplasmic death domain. TNF-a/TNFR1 interactions lead to pro-inflammatory responses.86,87 TNF- a/TNFR2 interactions reportedly promoted activation and expansion of murine Tregs in vivo.88 This interaction corre- lates with suppressive function and phenotypic stability of those Tregs.89 Furthermore, TNF-a expanded Tregs were protective against T1D90 as well as in the setting of infec- tions91 and septic shock.88 Additionally, TNFR2-deficient Tregs lost their capacity to control colitis92 and EAE.93 Using a selective agonist to increase binding specificity and target only mouse TNFR2 (TNC-scTNF80) Treg expansion, reduced inflammation in a model of chronic inflammation94 and established arthritis were reported.95
TNFRSF4 (OX-40)/TNFSF4 (OX-40-L) manipulation in pre-clinical allogeneic hematopoietic stem cell transplantation. Two decades ago, inhibition of the OX-40/OX-40-L axis was found to diminish murine lethal aGvHD in recipients post aHSCT.108 Indeed, infusion of pre-treated Tregs with OX-86 or intraperitoneal (i.p.) injection of OX-86 resulted in the inhibition of Treg suppressive activity on GvHD development.109 Additionally, when an OX-40L blocking antibody (KY1005) was combined with sirolimus in a non- human primate GvHD model, synergistic inhibition of T- cell activation while preserving post-HSCT Treg reconsti- tution was observed.110 Importantly, KY1005/sirolimus GvHD prophylaxis resulted in long-term GvHD-free sur- vival and significant control of aGvHD.110 Interfering with the OX-40L/OX-40 pathway in the setting of aHSCT did not reduce Treg reconstitution although impairment of this pathway resulted in impaired Treg development in young mice.100,101
TNFRSF9 (4-1BB)/TNFSF9 (4-1BB-L)
TNFRSF9 (4-1BB)/TNFSF9 (4-1BB-L) targeting to manipu- late Tregs in vivo. Analogous to OX-40, 4-1BB (CD137) is constitutively expressed on Tregs and is up-regulated upon activation on CD4 and CD8, B, NK and myeloid cells. CD137-L is the only known intercellular ligand for CD137 and is expressed on APC after activation, although the extracellular domain of 4-1BB binds to fibronectin and galectin-9. 4-1BB co-stimulatory activity is well appreciat- ed to promote proliferation and survival of CD8 T cells.111,112 However, this pathway can also induce Treg pro- liferation in vivo, as shown by experiments wherein Tregs were coated with 4-1BBL-Fc prior to infusion.113 Accordingly, agonistic anti-4-1BB mAb was shown to enhance the numbers of Tregs and ameliorate or inhibit disease in several experimental models of autoimmunity including, T1D,114 colitis,115 EAE,116 and psoriasis.117
TNFRSF9 (4-1BB)/TNFSF9 (4-1BB-L) manipulation in pre-clinical allogeneic hematopoietic stem cell transplantation. Several laboratories have investigated the implication of 4-1BB/4-1BBL interactions in GvHD and GvL. 4-1BB/4- 1BB-L interactions increased GvHD-induced lethality and allogeneic bone marrow rejection mediated by either CD4+ or CD8+ donor T cells. Moreover, treatment with agonistic anti-4-1BB mAb augmented GvL effects of delayed lymphocyte infusion in an acute myeloid leukemia (AML) model by stimulating an allogeneic anti- tumor response.118 Blockade of 4-1BB-L in F1 mice amelio- rated aGvHD, but aggravated cGvHD with high levels of IgE and anti-dsDNA IgG autoantibody.119 Furthermore, stimulation of 4-1BB using an agonistic mAb prevented cGvHD by inhibition of autoantibody production through activation induced donor CD4+ T-cell death accompanied by diminished host B-cell activation and decreased autoantibody production.120 As noted above, it has been demonstrated that stimulation of 4-1BB pro- motes in vivo Treg proliferation and suppressive activity.113 Following anti-4-1BB mAb (3H3) in vivo treatment, IL-2 production by memory T cells was increased resulting in the induction of Treg expansion in an Ag-independent manner.121 Notably, in this haploidentical (parent-into-F1) aGvHD model, host Tregs survived long term. Furthermore, pre-conditioning with anti-4-1BB mAb ameliorated GvHD by increasing Treg suppressive activi- ty against alloreactive donor T cells. When anti-4-1BB
TNFRSF1B (TNFR2)/TNF-a Treg manipulation in pre-clin- ical allogeneic hematopoietic stem cell transplantation. Serum TNF-a levels are elevated in individuals with GvHD. Due to its pleiotropic nature, this cytokine and the balance between its corresponding receptors modulate both GvHD and GvL. TNF-a in vivo selectively enhanced pro- liferation and activation of Tregs versus Tconv and in vitro increased Treg CTLA-4 and TGF-β levels.96 Notably, “unfavorable” (low) numbers of donor TNF-a-primed Tregs (1:10 Treg:Tconv), decreased aGvHD and augment- ed survival in recipients of a fully MHC-mismatched aHSCT.96 This diminution of aGvHD promoted by TNF- a primed Tregs was further explored by other investiga- tors demonstrating that this cytokine is produced by Tconv and the effect is dependent on TNFR2 expressed by Tregs.97 In vivo treatment of recipient mice before aHSCT with STAR2, a selective mouse TNFR2 agonist, resulted in expansion of radiation-resistant host Tregs concomitant with a reduction of aGvHD and increased survival. Importantly, STAR2 treatment did not interfere with the transplanted T-cell-mediated GvL or the immune response against infectious opportunistic (cytomegalocirus) pathogens.98
TNFRSF4 (OX-40)/TNFSF4 (OX-40-L)
TNFRSF4 (OX-40)/TNFSF4 (OX-40-L) targeting to manipu- late Tregs in vivo. OX-40 (CD134) is constitutively and highly expressed on murine Tregs and is up-regulated upon activa- tion on CD4+/CD8+ Tconv cells and to a lesser extent on NK, NKT cells and neutrophils. OX40 ligand, (OX-40-L, CD252), is expressed on a number of different cell types including activated professional APCs, activated T cells, NK cells, mast cells and endothelial cells.99 A role for OX-40 in the development, homeostasis and suppressive activity of Tregs has been implicated from studies using young knock- out (KO) OX-40-/- mice.100,101
The role of OX-40 on Treg expansion and function remains controversial. The use of agonistic anti-OX-40 mAb (OX-86) or APCs over-expressing OX-40L resulted in clear but weak proliferation and expansion of mouse Tregs in vivo and enhanced suppressive capacity in models of coli- tis and EAE.100-104 Addition of IL-2 together with anti-OX-40 mAb further amplified Treg expansion as well as suppres- sive activity in a heart transplant model.105 However, other studies where clone OX-86 was administered failed to induce Treg expansion and found inhibition of Treg func- tion in models of skin grafts and cancer.106,107
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haematologica | 2019; 104(7)