Page 35 - 2019_07 resto del Mondo-web

In vivo manipulation of Treg cells
Figure 2. Low-dose IL-2-based treatment of donors / recipients in pre-clinical graft-versus-host disease (GvHD) models. IL-2 administration alone or in combination has been extensively utilized in several mouse models to ameliorate GvHD. The success of this strategy relies on the importance of the IL-2/IL-2R signaling pathway on Treg survival, proliferation and suppressive function in vivo. HvG: host-versus-graft.
observed in a xenogeneic GvHD model.79 In a murine major-MHC mismatched aHSCT, no effect occurred when treating recipients with LD IL-2 (twice daily) alone. However, the concomitant administration of the mTOR inhibitor sirolimus (0.5 kg/mg daily) in the first week post transplant improved survival and diminished aGvHD. Importantly, in vivo treatment with IL-2 plus sirolimus resulted in higher donor Treg expansion versus either IL-2 or sirolimus alone. These donor-derived expanded Tregs comprised both expanded natural Tregs and increased conversion of induced Tregs.80 Initially in a human trial, superior Treg reconstitution and aGvHD prevention was observed in patients treated with the combination of sirolimus and tacrolimus versus peri-transplant methotrex- ate and tacrolimus.81 In order to improve Treg recovery and based on previous reports, LD IL-2 administration (3 times/wk for 90 days) post transplant was added to the sirolimus/tacrolimus treatment regimen in 20 patients (clinicaltrials.gov identifier: 01927120) (Online Supplementary Table S1). This phase II trial demonstrated augmented peripheral blood Treg reconstitution in the first month post HSCT in the LD IL-2 (200,000 IU/m2) plus sirolimus/tacrolimus treated group compared to sirolimus/tacrolimus alone. However, this early Treg expansion was not maintained and did not ameliorate
82
acute or cGvHD. National Institutes of Health clinical tri-
als involving IL-2 and aHSCT are summarized (Online Supplementary Table S1).
B. Treatment of donors: pre-clinical and clinical models. Using an MHC-haploidentical aHSCT model, LD IL-2 treatment
in donor mice was inadequate as a GvHD prevention strategy. Although IL-2 administration over five days ele- vated Treg levels in the graft, no improvement in recipient weight loss or survival was observed.79 These results were attributed to a <1:1 ratio of Tregs:Tconv using a LD IL-2 only Treg expansion strategy. Notably, when donor mice were treated with Dex (5 mg/kg daily) and LD IL-2 for three days, higher Treg levels were observed in compari- son to treatment with either reagent alone. In a fully- MHC mismatched aHSCT, mice receiving Dex+IL-2 pre- treated donor cells exhibited improvement in survival and diminution of aGvHD83 (Figure 2). We are currently not aware of any studies reporting the use of T cells from IL- 2 treated HSCT human donors. A recent report noted that treatment of healthy individuals with ultra LD rhIL-2 (50,000-200,000 U/m2/day) for five days elevated periph- eral Tregs with augmented suppressive activity without detection of acute or long-term on/off-target effects.84
TNFR super family
The TNF family currently comprises 29 receptors and 19 ligands. In this section, we discuss those members report- ed to be capable of regulating the Treg compartment in vivo including TNFR2, OX-40, 4-1BB and TNFRSF25.85
TNFRSF1B (TNFR2)/TNF-a
TNFRSF1B (TNFR2)/TNF-a targeting to manipulate Tregs
in vivo. TNFR2 is highly and constitutively expressed on murine Tregs and other immune cells and further up-reg- ulated after activation. It is also found on some endothelial and cells of the nervous system whereas TNFR1 is ubiqui-
haematologica | 2019; 104(7)
1313