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S. Copsel et al.
and T1D,144 as well as inflammation, e.g. arthritis,145,146 glomerulonephritis147 and trypanosomiasis-associated inflammation.148 Furthermore, CD28SA expanded Tregs prolong graft survival in experimental models of solid organ (renal/heart) transplantation.149,150
CD28/CD80/86 (B7.1/2) manipulation in pre-clinical allo- geneic hematopoietic stem cell transplantation. A single dose of CD28SA (clone JJ316) administration in vivo to Lewis rats induced a selective 4-fold expansion of Tregs over Tconv. Adoptive transfer of anti-CD28 mAb treated splenocytes in a rat transplantation model reduced lethality and sup- pressed GvHD. Importantly, this therapeutic effect was mediated by expanded Tregs detected in high levels after transfer of anti-CD28 mAb-treated lymphocytes.151 Moreover, this mAb was utilized to treat F1 rat recipients at different time-points pre- or post aHSCT. GvHD mor- tality was absent or suppressed when recipients were treated with anti-CD28, three days before T-cell transfer or on day 0, respectively. In contrast, no protective effect was observed in recipients treated on day 7 or 10. Importantly, GvHD lethality reduction was mediated by anti-CD28SA selective Treg expansion in an antigen-spe- cific manner.152 In a murine major-MHC mismatched aHSCT model, adoptive transfer of unfractionated poly- clonal activated donor Tregs, with CD28SA (D665) signif- icantly reduced GvHD-associated clinical signs and histopathological changes. Notably, this mAb adminis- tered to recipients or in vitro pre-stimulated donor T cells conserved a potent anti-lymphoma (GvL) response.153 The CD28SA in vitro approach may have clinical potential for patients because an anti-human CD28 mAb (TGN1412) induced a cytokine storm during the first in human clinical study.154
IL-33/ST2
IL-33/ST2 targeting to manipulate Tregs in vivo. IL-33, an IL-1 family member, is constitutively expressed in epithe- lial and endothelial cells at barrier sites where it functions as an endogenous danger signal in response to tissue dam- age. IL-33 is also a pleiotropic cytokine found in fibroblas- tic reticular cells of secondary lymphoid organs. It binds to the ubiquitously expressed IL-1R accessory protein (IL- 1RAcP) and the more selectively expressed receptor ST2. The ST2 receptor is constitutively expressed on innate (mast cells, ILC2s, eosinophils, basophils, NK cells) and adaptive immune cells (Tregs, Th2, NKT) and up-regulat- ed upon activation on Th1 and cytotoxic T cells. A soluble form of ST2 can be produced by alternative splicing and serves as a decoy receptor to limit IL-33 signaling.155,156 Notably, the quantitative differences in ST2 expression among different T-cell subsets potentially could lead to competition for IL-33. Tissue Tregs, which express consti- tutively high levels of ST2, could therefore sequester IL-33 from inflammatory cells which would give them an advantage over effector T cells in situations of limited IL- 33. Soluble ST2 released from intestinal tissue has recently been identified as an important biomarker of GvHD that is highly predictive for early post-HSCT mortality.157
Several reports have shown that administration of IL-33 leads to a ST2 dependent expansion of Tregs in vivo.158,159 ST2+ Tregs represent an activated subset of Tregs and are preferentially expressed in non-lymphoid tissues, like lung (20-30% of Treg), gastrointestinal tract (GI) (approx. 20%), and liver (50-60%).160-162 ST2+ Tregs exhibit superior suppressive function compared to ST2- Tregs.161 In a model
of allogeneic heart transplantation, IL-33 expanded ST2+ Tregs migrated to the graft and prolonged survival.163,164 Furthermore, in a model of collagen induced rheumatoid arthritis, IL-33 expanded ST2+ Tregs suppressed clinical and histological signs of arthritis.165 In addition, IL-33 sig- naling is apparently crucial for liver Treg expansion, accu- mulation and suppression of infection after murine CMV infection.166 A combination of IL-33 together with IL-2 administration has a synergistic effect with regard to Treg expansion.56 This group also generated a hybrid fusion protein between those 2 cytokines, IL-233, which bears the activities of both. IL-233 treatment significantly increased the number of Tregs in blood, spleen and renal compartments and prevented ischemia reperfusion injury more efficiently than a mixture of IL-2 and IL-33.
IL-33/ST2 manipulation in pre-clinical allogeneic hematopoi- etic stem cell transplantation. In aHSCT, the IL-33/ST2 axis has recently emerged as a novel therapeutic target for GvHD. In particular, high levels of IL-33 and ST2 were detected in recipients post conditioning, contributing to lethal aGvHD via donor TH1 alloimmune responses.167 Therefore, transplants involving either IL-33-/- recipients, ST2-/- donor T cells or IL-33 antagonist (ST2-Fc fusion pro- tein) administration resulted in increased recipient sur- vival.167 Conversely, in vivo administration of peri-aHSCT IL-33 (day -10 to day 4) to recipients induced a diminution of clinical GvHD scores and prolonged survival. This pro- tection against GvHD was promoted by IL-33-expanded recipient ST2+ Tregs (persisted after total body irradiation) which controlled M1 macrophage activation and reduced effector T-cell levels. The underlying mechanism of IL- 33/ST2-induced Treg proliferation was mediated by acti- vation of p38 MAPK.168 Subsequent studies found that transfer of ST2-/- donor Tregs affect diminished protection of GvHD after an MHC-mismatched aHSCT.167 We are unaware of any ongoing clinical trials regulating the IL- 33/ST2 pathway in vivo to manipulate Tregs.
“Unintentional” effects on the Treg compartment: potential impact in hematopoietic stem cell transplantation
While direct targeting of molecules on the Treg cell sur- face can induce their expansion, unintentional but clinical- ly useful procedures in HSCT including extracorporeal photopheresis (ECP),169 donor stem cell mobilization,170-172 PTCy,173,174 azacytidine,175 JAK1/2 inhibitors176,177 and ROCK1/2 inhibitors178,179 also affect the Treg compartment although to a lesser extent than intentional interventions. Although Tregs have demonstrated promising results in regulating GvHD, combining their regulatory activity with other strategies being used in the clinic may further improve transplant outcomes for patients. Therefore, if strategies partially diminish or do not interfere with Tregs, augmenting the compartment should be useful. For exam- ple, in addition to alloreactive Tconv deletion, Tregs are reportedly needed for optimal PTCy (day 3-4) GvHD pro- phylaxis.180,181 Treg expansion subsequent to PTCy may, therefore, augment the effectiveness of this reagent. In contrast, if strategies elevate Tregs this should provide additional benefit and further enable synergistic expan- sion. For example, azacytidine (AzaC), like PTCy, prefer- entially inhibits Teff versus Treg proliferation, but addi- tionally converts Teffs to Tregs via hypomethylation of the Foxp3 promoter.175 Pre-clinical and clinical studies have
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haematologica | 2019; 104(7)