Table 2.

Summary of the studies evaluating the use of vitamin D and its analogs (alone or in combination with immunosuppressive agents and/or other anti-inflammatory agents, such as omega-3 PUFAs) in animal models of allogeneic islet transplantation. Abbreviations: DCs, dendritic cells; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IL, interleukin; MMF, mycophenolate mofetil; MST, mean survival time; PUFAs, polyunsaturated fatty acids; STZ, streptozotocin; TNF-α, tumor necrosis factor-alpha.

Study Treatment	Study Treatment Duration	Animal Model	Main Findings	References
Calcitriol in combination with MMF	MMF and/or calcitriol were administered from the day before transplantation and continued until day 30 after transplantation	BALB/c STZ-induced diabetic mice receiving allogeneic islets under the kidney capsule (pancreatic islets were isolated from C57BL/6 (B6) mice)	MMF (100 mg/kg/day) and calcitriol (5 μg/kg/three times a week) combination therapy was associated with significantly longer islet graft survival compared to MMF or calcitriol alone (% of graft survival 70 days after transplantation: 85%, 52%, 48%, respectively). MMF and calcitriol combination therapy was associated with significantly higher resistance to islet graft rejection in comparison to MMF or calcitriol alone (% of graft survival 100 days after transplantation: 72.2%, 33.3%, 52.7%, respectively).	[82]
Calcitriol in combination with MMF	MMF and/or calcitriol were administered from the day before transplantation and continued until day 30 after transplantation	BALB/c STZ-induced diabetic mice receiving allogeneic islets under the kidney capsule (pancreatic islets were isolated from C57BL/6 (B6) mice)	MMF (100 mg/kg/day) and calcitriol (5 μg/kg/three times a week) combination therapy inhibited the peri-graft recruitment of macrophages and DCs and decreased IL-12 secretion. MMF plus calcitriol increased the frequency of CD4+CD25+ regulatory T cells in the spleen and in the kidney lymph nodes draining the islet graft. These cells were able to transfer long-term transplant tolerance in naïve syngeneic recipient mice (up to 40 days).	[83]
Calcitriol-modulated DCs	Transplant recipient mice received three intravenous transfers of calcitriol-modulated murine DCs on days −10, −3 and 0 before transplantation	C57BL/6 alloxan-induced diabetic mice receiving allogeneic islets under the kidney capsule (pancreatic islets were isolated from BALB/c donor mice). Bone marrow cells were harvested from C57BL/6 mice and subsequently induced to differentiate into mature DCs (10 day-culture). The in vitro DC generation was performed in the absence (control DCs) or presence (10−8 M) of calcitriol (calcitriol-modulated DCs). In order to perform the DC transfer experiment in the islet allotransplantation model, DCs were pulsed during the last 48 hours of culture with BALB/c islet antigen (BALB/c islet antigen-loaded control DCs).	5 out of 7 recipient mice receiving calcitriol-modulated DCs before islet allotransplantation did not experience hyperacute graft rejection, that was instead observed in all 4 mice receiving BALB/c islet antigen-loaded control DCs. Islet allograft survival was not consistently prolonged in mice receiving calcitriol-modulated DCs compared to mice who did not receive any immunomodulatory treatment (untreated group): MST, 11.4 ± 2.2 days vs. 9.0 ± 1.0 days, respectively.	[39]
Vitamin D3 plus omega-3 PUFAs (EPA and DHA)	Vitamin D3 and/or omega-3 PUFAs were administered on days 0, 1 and 2 after transplantation. Daclizumab was administered intravenously for induction immunosuppression, at a dose of 0.05 mg/kg body weight before transplantation (day 0) and on days 1 and 2 after transplantation.	STZ-induced diabetic Wistar albino rats receiving allogeneic intraportal islet transplantation	Vitamin D3 (5 μg/kg) plus EPA and DHA (7 mg/kg) significantly reduced the increase in serum levels of TNF-α at days 1 and 2 after transplantation compared to control group and rats treated with vitamin D3 or omega-3 PUFAs alone.	[84]