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1.
J Pharm Sci ; 90(5): 625-37, 2001 May.
Article in English | MEDLINE | ID: mdl-11288107

ABSTRACT

Inosine monophosphate dehydrogenase (IMPDH) is an essential rate-limiting enzyme in the purine metabolic pathway, catalyzing the de novo synthesis of guanine nucleotides required for lymphocyte proliferation. IMPDH has therefore been an attractive target for developing immunosuppressive drugs (e.g., CellCept and mizoribine). Here we describe the immunosuppressive activity of VX-497, a novel noncompetitive inhibitor of IMPDH. VX-497 (MW 452.5) is orally bioavailable and inhibits the proliferation of primary human, mouse, rat, and dog lymphocytes at concentrations of approximately 100 nM. The inhibitory effect of VX-497 on lymphocytes is reversed in the presence of exogenous guanosine, but not in the presence of adenosine or uridine, confirming that the antilymphocytic activity of VX-497 is specifically due to inhibition of IMPDH. The antiproliferative effect of VX-497 in cells is also reversed within 48 h of its removal. Based on evaluation of VX-497 in several lymphoid and nonlymphoid cells, the antiproliferative effect of VX-497 is observed to be most pronounced on lymphoid and keratinocyte cells as compared with fibroblasts. In vivo, oral administration of VX-497 inhibits the primary IgM antibody response in a dose-dependent manner, with an ED(50) value of approximately 30-35 mg/kg in mice. Single daily dosing of VX-497 is observed to be as effective as twice-daily dosing in this model of immune activation. These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation.


Subject(s)
B-Lymphocytes/drug effects , Carbamates/pharmacology , Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Keratinocytes/drug effects , Phenylurea Compounds/pharmacology , T-Lymphocytes/drug effects , Animals , B-Lymphocytes/physiology , Carbamates/chemistry , Cell Line , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Humans , Immunosuppressive Agents/pharmacology , Keratinocytes/physiology , Male , Mice , Mice, Inbred C57BL , Phenylurea Compounds/chemistry , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , T-Lymphocytes/physiology
2.
Lab Anim Sci ; 42(2): 146-51, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1351111

ABSTRACT

Three of 14 cynomolgus monkeys given the highest dose of an immunosuppressive drug in a 6-month toxicology study developed B virus (Herpesvirus simiae) oral lesions after 3 months of dosing. This necessitated early removal of all high-dose monkeys from the study due to concerns related to B virus. The incidence and severity of parasitic (Oesphagostomum sp.) lesions of the large intestine were also increased in high-dose animals. Both B virus and Oesophagostomum are enzootic in macaques, and the lesions caused by them were considered secondary to chronic immunosuppression caused by the highest dose of the test compound. Evidence of immunosuppression included decreased lymphocyte counts (B-cells; CD2 and CD8 T-cells), histopathologic evidence of lymphoid suppression, and serum-induced inhibition of lymphocyte mitogen responses. Pathogenesis of the B virus was apparently associated with both activation of latent virus as well as transmission of active virus. Approaches for virologic monitoring of primates and for ensuring optimal safety for primate handlers are discussed.


Subject(s)
Herpesviridae Infections/veterinary , Herpesvirus 2, Saimiriine , Macaca fascicularis , Monkey Diseases/microbiology , Mouth Diseases/veterinary , Tumor Virus Infections/veterinary , Animals , Antigens, Differentiation, T-Lymphocyte/immunology , CD2 Antigens , Female , Herpesviridae Infections/immunology , Herpesviridae Infections/pathology , Herpesvirus 2, Saimiriine/growth & development , Immunosuppression Therapy , Immunosuppressive Agents/adverse effects , Lymphocyte Activation/immunology , Male , Monkey Diseases/immunology , Monkey Diseases/pathology , Mouth Diseases/immunology , Mouth Diseases/pathology , Random Allocation , Receptors, Immunologic/immunology , Tumor Virus Infections/immunology , Tumor Virus Infections/pathology , Virus Activation
5.
Scand J Immunol ; 33(2): 161-73, 1991 Feb.
Article in English | MEDLINE | ID: mdl-1826793

ABSTRACT

Mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase, in nanomolar concentrations blocks proliferative responses of cultured human, mouse and rat T lymphocytes and B lymphocytes to mitogens or in mixed lymphocyte reactions. The inhibitory effect of MPA on lymphocyte proliferation is reversed by addition to culture media of deoxyguanosine or guanosine but not by addition of deoxyadenosine or adenosine. The findings suggest that the principal mechanism of action of low concentrations of MPA is depletion of deoxyguanosine triphosphate which is required for DNA synthesis. In immunosuppressive doses, MPA does not affect the formation of IL-1 by LPS-activated human peripheral blood monocytes. Unlike cyclosporin A and FK-506, MPA does not inhibit the formation of IL-2 and the expression of the IL-2 receptor in mitogen-activated human T lymphocytes. MPA suppresses mixed lymphocyte reactions when added 3 days after their initiation. These findings suggest that MPA does not inhibit early responses of T and B lymphocytes to mitogenic or antigenic stimulation but blocks the cells at the time of DNA synthesis. The cytostatic effect of MPA is more potent on lymphocytes than on other cell types, such as fibroblasts and endothelial cells. MPA also inhibits antibody formation by polyclonally activated human B lymphocytes. MPA is an immunosuppressive agent reversibly inhibiting proliferation of T and B lymphocytes and antibody formation, with a profile of activity different from that of other immunosuppressive drugs. Human T and B lymphocytic and promonocytic cell lines are highly sensitive to the antiproliferative effects of MPA, whereas the erythroid precursor cell line K562 is less susceptible. The effect of MPA on cells of the monocyte-macrophage lineage could exert long-acting anti-inflammatory activity. MPA or analogues may have therapeutic utility in diseases such as rheumatoid arthritis, for prevention of allograft rejection and in lymphocytic or monocytic leukaemias and lymphomas.


Subject(s)
B-Lymphocytes/drug effects , Deoxyguanine Nucleotides/pharmacology , Immune Tolerance/drug effects , Mycophenolic Acid/pharmacology , T-Lymphocytes/drug effects , Animals , Cell Line , Cytokines/metabolism , DNA/drug effects , Female , Fibroblasts/drug effects , Humans , Lymphocyte Activation/drug effects , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mycophenolic Acid/antagonists & inhibitors , Rats , Rats, Inbred Strains , Receptors, Interleukin-2/metabolism , Spleen/cytology
6.
Proc Natl Acad Sci U S A ; 87(4): 1305-9, 1990 Feb.
Article in English | MEDLINE | ID: mdl-2304900

ABSTRACT

Some monoclonal antibodies (mAbs) against interleukin (IL) 1 alpha have been found to activate antigen-presenting cells (APC, human peripheral blood monocytes and B lymphocytes), so that unstimulated T lymphocytes cultured with them are induced to proliferate and secrete IL-2. Control mAbs of the same isotypes and mAbs against IL-1 beta do not activate APC. In the absence of APC, mAbs against IL-1 alpha do not induce proliferation of T lymphocytes. Mitomycin C-treated activated APC still induce T-cell proliferation. Proliferation of T lymphocytes cannot be induced by culture supernatants and requires contact with APC activated by mAbs against IL-1 alpha. The observations imply that surface membrane IL-1 alpha can function as a triggering molecule on APC, which could play an important role in the initiation of immune responses by T lymphocytes.


Subject(s)
Antibodies, Monoclonal/immunology , Interleukin-1/immunology , Lymphocyte Activation , T-Lymphocytes/immunology , Animals , Antigen-Presenting Cells/immunology , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Cells, Cultured , Humans , Immunoglobulins/analysis , Interleukin-1/pharmacology , Mice , Mice, Inbred C3H , Monocytes/immunology , Recombinant Proteins/immunology , Recombinant Proteins/pharmacology , T-Lymphocytes/cytology , T-Lymphocytes/drug effects
8.
Infect Immun ; 15(1): 322-8, 1977 Jan.
Article in English | MEDLINE | ID: mdl-319064

ABSTRACT

C3H/Bi mice developed autoantibodies after repeated inoculations of isolated membranes from primary tissue cultures of a syngeneic ascites lymphoma in which Newcastle disease virus had grown. This was in addition to the tumor transplantation resistance and cytotoxic antibodies previously demonstrated. The complement-fixing antibodies were completely removed from sera by adsorption with ascites tumor cells but only partially by normal mouse liver powder or C3H/Bi erythrocytes. With continued immunization, antibodies to deoxynucleoprotein and heterophile reagins also appeared. After several months, mice showing these serological reactions died with a wasting disease characterized by loss of lymphoid tissue and scarred, atrophied kidneys. No significant antibody response or autoimmune disease occurred in mice receiving membranes from uninfected syngeneic ascites lymphoma.


Subject(s)
Antigens, Viral/biosynthesis , Autoantibodies , Cell Membrane/immunology , Lymphoma/immunology , Newcastle disease virus/immunology , Animals , Antibodies, Antinuclear/analysis , Autoimmune Diseases/mortality , Complement Fixation Tests , Cytopathogenic Effect, Viral , Immunosorbent Techniques , Mice , Mice, Inbred C3H , Species Specificity
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