MC1288, a vitamin D analog, prevents acute graft-versus-host disease in rat bone marrow transplantation

Abstract

Summary:The major obstacle to successful bone marrow transplantation (BMT) is graft-versus-host disease (GVHD). Vitamin D analogs have shown their efficacy in solid organ transplantation. The purpose of this study was to investigate the suitability of a novel vitamin D analog, MC1288, in the prevention of acute GVHD in a rat BMT model. Allogeneic BMT were performed from Lewis to BN rats (n = 18). The animals were divided into four groups: an untreated control group, MC1288, cyclosporin A (CsA), and MC1288 + CsA-treated groups. Rats were harvested for histology and immunohistochemistry on day 20 after BMT. Histological changes for GVHD in liver, skin, and spleen were thickening associated with transplant arteriosclerosis, or chronic rejection, in a rat aortic transplant model. 7 In addition to their immunosuppressive effects, we and others have shown that vitamin D analogs have anti-leukemic effects both in vitro and on de novo patient samples. 8 The major obstacle in using natural vitamin D or its early analogs for treatment has been hypercalcemia before therapeutic concentrations could be reached. 9,10 This problem has now been solved with novel analogs with lesser calcemic activity. 7,8 MC 1288 is a 20-epi-1,25(OH) 2 D 3 , differing from 1,25(OH) 2 D 3 by altered stereochemistry of the methyl group at carbon 20 in the side chain of the molecule (Figure 1). We have previously shown that MC1288 is well tolerated in rats in vivo. It did not induce hypercalcemia during the first month of treatment although in 3 months, the serum calcium level increased by 30%. 7 The purpose of this study was to investigate the suitability of MC1288 in the prevention of acute graft-versushost disease (GVHD) in a rat bone marrow transplantation (BMT) model. Here, we studied the effects of MC1288 on the clinical course and histological manifestations of acute GVHD after allogeneic BMT. Materials and methods Bone marrow transplantation (BMT)Allogeneic bone marrow transplantations were performed using adult Brown Norway (BN; RT1 l ) rats as recipients and 10-week-old Lewis (LEW; RT1 n ) rats as bone marrow cell donors. The cells were collected by flushing the femurs with saline. The recipient animals were irradiated with 960 rad (Varian Climac 600c, 6 MV photon irradiation, distance 120 cm, field size 40 × 40 cm 2 ) prior to BMT. After 24 h, 60-80 × 10 6 mononuclear bone marrow cells from LEW rats were injected into BN recipients.

Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia

“…55 In allogeneic HSCT, the use of a vitamin D analog, MC 1288, has been shown to prevent acute GvHD in a rat model. 56 Middleton et al 57 in a study with 88 transplant recipients and 80 of their sibling donors, found that the ApaI allele when present in the patients' genotype was associated with severe acute GVHD. Analysis of donor polymorphisms found that survival was substantially lower in patients' receiving grafts from ApaI AA donors.…”

New Developments in Allotransplant Immunology

“…Furthermore, vitamin D analogues can prolong graft survival and prevent GVHD in animal studies. 51,52 Polymorphism in the VDR intron 8 region 53 and in intron 1 of the estrogen receptor alpha (ERα) 54 genes have been associated with both occurrence of GVHD and likelihood of survival following allo-BMT. In HLA-matched sibling BMT 53 the Apo1 "a" VDR allele in the patient was associated with severe acute GVHD, but with improved survival if present in the donor.…”

Variations in 1α,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 serum levels during allogeneic bone marrow transplantation

“…Accordingly, it has been shown that vitamin D analogs prevent acute GvHD in rat BMT and that the VDR gene polymorphism associates with GvHD and survival. 4,5 Up to now, no data are available on the endogenous serum levels of vitamin D metabolites during the course of BMT. In this study we measured 25-hydroxyvitamin D 3 (25(OH)D 3 ) and 1,25(OH) 2 D 3 in consecutive serum samples of 48 patients before and after allogeneic BMT.…”