pyrimidinones and Graft-vs-Host-Disease

Recent preclinical and clinical investigations indicate that phototherapy and photochemotherapy may have applications that go far beyond their "traditional" roles in the treatment of skin disorders, selected solid tumors, and neonatal hyperbilirubinemia. Bone marrow transplantation is one area that may benefit substantially from these new developments. This review focuses on new applications of phototherapy and photochemotherapy that pertain to the inactivation of tumor cells in autologous bone marrow grafts, the prevention and treatment of acute and chronic graft-versus-host disease, the prevention of transfusion-induced allosensitization and graft rejection, and the inactivation of pathogenic viruses and parasites in bone marrow grafts and blood products.

Topics: Animals; Antiviral Agents; Blood; Bone Marrow Purging; Bone Marrow Transplantation; Graft Rejection; Graft vs Host Disease; Humans; Immunization; Infection Control; Mice; Neoplasms; Neoplastic Stem Cells; Photochemotherapy; Photosensitizing Agents; Phototherapy; Pyrimidinones; Radiation-Sensitizing Agents; Transfusion Reaction

Topics: Adolescent; Adult; Animals; Bleomycin; Bone Marrow; Bone Marrow Transplantation; Cell Separation; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Etoposide; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lysophosphatidylcholines; Methylprednisolone; Neoplasms, Experimental; Phospholipid Ethers; Pyrimidinones; Transplantation, Autologous; Transplantation, Isogeneic

Recent preclinical and clinical investigations indicate that phototherapy and photochemotherapy may have applications that go far beyond their "traditional" roles in the treatment of skin disorders, selected solid tumors, and neonatal hyperbilirubinemia. Bone marrow transplantation is one area that may benefit substantially from these new developments. This review focuses on new applications of phototherapy and photochemotherapy that pertain to the inactivation of tumor cells in autologous bone marrow grafts, the prevention and treatment of acute and chronic graft-versus-host disease, the prevention of transfusion-induced allosensitization and graft rejection, and the inactivation of pathogenic viruses and parasites in bone marrow grafts and blood products.

Topics: Animals; Antiviral Agents; Blood; Bone Marrow Purging; Bone Marrow Transplantation; Graft Rejection; Graft vs Host Disease; Humans; Immunization; Infection Control; Mice; Neoplasms; Neoplastic Stem Cells; Photochemotherapy; Photosensitizing Agents; Phototherapy; Pyrimidinones; Radiation-Sensitizing Agents; Transfusion Reaction

Topics: Adolescent; Adult; Animals; Bleomycin; Bone Marrow; Bone Marrow Transplantation; Cell Separation; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Etoposide; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lysophosphatidylcholines; Methylprednisolone; Neoplasms, Experimental; Phospholipid Ethers; Pyrimidinones; Transplantation, Autologous; Transplantation, Isogeneic

Rapid immune reconstitution without developing graft-versus-host disease (GVHD) is required for the success of allogeneic hematopoietic stem cell transplantation. Here, we analyzed the effects of pharmacological MEK inhibition on human polyclonal T-cell reconstitution in a humanized mouse GVHD model utilizing deep sequencing-based T-cell receptor (TCR) repertoire analysis. GVHD mice exhibited a skewed TCR repertoire with a common clone within target organs. The MEK inhibitor trametinib ameliorated GVHD and enabled engraftment of diverse T-cell clones. Furthermore, trametinib also ameliorated GVHD sparing diverse T cell repertoire, even when it was given from day 15 through 28. Although tacrolimus also reduced development of GVHD, it disturbed diverse T cell reconstitution and resulted in skewed TCR repertoire. Thus, trametinib not only suppresses GVHD-inducing T cells but also promotes human T cell reconstitution in vivo, providing a novel rationale for translational studies targeting human GVHD.

Topics: Animals; Cells, Cultured; Clone Cells; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Janus Kinase 3; Mice; Mice, Knockout; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptors, Antigen, T-Cell; T-Lymphocytes; Tacrolimus; Transplantation, Heterologous

The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.

Topics: Animals; Graft vs Host Disease; Graft vs Tumor Effect; Hematopoietic Stem Cell Transplantation; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

Merocyanine 540-mediated photodynamic therapy (MC540-PDT) has been used in clinical trials for the purging of autologous hematopoietic stem cell grafts. When the same combinations of dye and light were applied to human peripheral blood lymphocytes, a broad range of T- and B-cell functions were impaired, prompting speculations about a potential role of MC540-PDT in the prophylaxis of graft-versus-host disease (GVHD). We here report on the effects of MC540-PDT on in vitro functions of murine lymphocytes as well as a preliminary evaluation of MC540-PDT for the prevention of GVHD in murine models of allogeneic bone marrow transplantation. Mixed lymphocyte reactions, proliferative responses to lectins, interleukin-2 and lipopolysaccharide, T-cell-mediated lysis, and NK activity were all inhibited by moderate doses of MC540-PDT. Whether MC540-PDT reduced the incidence and/or the severity of GVHD in murine models of allogeneic hematopoietic stem cell transplantation depended on the composition of the mismatched grafts and the intensity of the preparative regimen. MC540-PDT was only beneficial (i.e. reduced the incidence and/or severity of GVHD) when the spleen cell content of grafts was low and/or the radiation dose of the preparative regimen was not myeloablative, and, therefore, may have encouraged mixed chimerism.

Topics: Animals; B-Lymphocytes; Body Weight; Bone Marrow Cells; Bone Marrow Transplantation; Cell Proliferation; Cell Survival; Female; Graft vs Host Disease; Killer Cells, Natural; Light; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Photochemotherapy; Photosensitizing Agents; Pyrimidinones; T-Lymphocytes; Transplantation, Homologous

Purine nucleoside phosphorylase (PNP) deficiency in humans produces a relatively selective depletion of T-cells. Inhibitors of PNP are therefore of interest as potential T-cell selective immunosuppressive agents. BCX-1777 is a potent inhibitor of PNP and in vitro T-cell proliferation. Inhibition of human T-cells by BCX-1777 and deoxyguanosine (dGuo) is accompanied by deoxyguanosine triphosphate (dGTP) accumulation. Unlike human T-cells, mouse, rat, dog and monkey T-cells are neither inhibited (IC50>100 microM) nor accumulate dGTP in the presence of BCX-1777 and dGuo. Cells pretreated with BCX-1777 and dGuo for 24 h (to elevate dGTP levels) prior to stimulation demonstrated 80% inhibition similar to the inhibition observed with cells treated with BCX-1777 and dGuo during the stimulation and proliferation process. This further confirms that inhibition of T-cells is due to the accumulation of dGTP in these cells. Deoxynucleotide (dNTP) analysis of the cells treated with BCX-1777 and dGuo for 48 h showed no significant change in deoxycytidine triphosphate (dCTP) and deoxyadenosine triphosphate (dATP) pools. However, a decrease (2-fold) in thymidine triphosphate (dTTP) pools, and a large increase in dGTP pools (15-fold) were observed. Results from various groups have shown that alteration in the dNTP supply results in DNA fragmentation and cell death with characteristics of apoptosis. Indeed, apoptosis is observed in human T-lymphocytes treated with BCX-1777 and dGuo. To compare the in vivo efficacy of BCX-1777 with another potent T-cell inhibitor, cyclosporin, these drugs were tested in a xenogeneic graft-vs.-host disease model (XGVHD). In this model, human lymphocytes are engrafted into severe combined immunodeficient mice (SCID) mice inducing severe XGVHD. The efficacy of BCX-1777 in the XGVHD model was comparable to cyclosporin and a combination of BCX-1777 and cyclosporin treatment showed a trend towards increased efficacy compared to cyclosporin alone. These results suggest that BCX-1777 may be useful for the treatment of disease characterized by activated T-cell responses.

Topics: Animals; Cyclosporine; Deoxyguanine Nucleotides; Dogs; Drug Therapy, Combination; Graft vs Host Disease; Growth Inhibitors; Humans; Immunosuppressive Agents; Lymphocytes; Macaca fascicularis; Mice; Mice, Inbred BALB C; Mice, SCID; Purine Nucleosides; Pyrimidinones; Pyrroles; Rats; Rats, Sprague-Dawley; Survival Rate; Transplantation, Heterologous

Topics: Animals; Bone Marrow Transplantation; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Leukemia; Light; Neoplasms; Pyrimidinones; Transplantation, Autologous