mercaptopurine and Immunologic-Deficiency-Syndromes

The development of our knowledge of the immune system has been reviewed and evidence presented of the need for a rapid rate of purine synthesis de novo for the proliferative events in this process. The mechanism of the inhibition of the immune system in a model of ADA deficiency has been studied intensively and considerable indirect evidence obtained of adenosine toxicity as a possible mediator of a reversible inhibition of proliferation of T-cells and to a slightly lesser extent B-cells. A secondary inhibition of ADA by inosine accumulation in PNP deficiency is proposed as a unifying hypothesis in which a somewhat lesser adenosine toxicity would inhibit proliferation only only of T-cells. The correction of the immune response by addition of ADA both in vitro and in vivo provides strong evidence in favor of this view. In HPRT deficiency no evidence was found of a gross impairment of the immune system; however, the HPRT enzyme is required for inhibition of the immune response by 6MP in a variety of systems using different mitogenic stimuli.

Topics: Adenine; Adenosine; Adenosine Deaminase; Antibody Formation; Hormones; Humans; Immunity, Cellular; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Inosine; Lesch-Nyhan Syndrome; Liver; Lymphocyte Activation; Lymphocytes; Mercaptopurine; Models, Biological; Nucleoside Deaminases; Pentosyltransferases; Purine-Nucleoside Phosphorylase; Purines; Synaptic Transmission; Uridine

We report a 5.5-year-old boy who underwent autologous peripheral blood stem cell transplantation for high-risk acute lymphoblastic leukemia and who had two abdominal masses develop 6 months later. Macroscopically complete resection of the abdominal tumors was performed and revealed a well-differentiated leiomyosarcoma. Smooth muscle tumors, benign or malignant, are increasingly recognized in children with various immunodeficiencies; the association with acute lymphoblastic leukemia is rarely described.

Topics: Abdominal Neoplasms; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child, Preschool; Cortisone; Disease Susceptibility; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunologic Deficiency Syndromes; Leiomyosarcoma; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Neoplasms, Second Primary; Remission Induction; Transplantation Conditioning; Transplantation, Autologous; Vincristine; Whole-Body Irradiation

Three patients with the Lesch-Nyhan syndrome were found to have normal delayed hypersensitivity, peripheral-blood T-lymphocyte counts, lymphocyte responses to P.H.A., and serum IgM, IgA, and IgE levels. However, the percentages of B-lymphocytes, IgG levels, serum-isohaemagglutinin titres, and lymphocyte responses to pokeweed mitogen (P.W.M.) were subnormal. These observations suggest that activity of the salvage pathway of purine synthesis catalysed by hypoxanthine-guanine phosphoribosyl transferase (H.G.P.R.T.) is not required for the responses of T-lymphocytes to mitogenic or antigenic stimulation, but may contribute to the proliferation and function of B lymphocytes. The major role of the de-novo pathway of purine synthesis in human lymphocyte responses to mitogenic or antigenic stimulation is shown by the effects of inhibitors of this pathway, including immunosuppressive agents, and by the effects of congenital deficiency or inhibition of adenosine deaminase.

Topics: Adenosine Deaminase; Adolescent; Azaserine; B-Lymphocytes; Child; Child, Preschool; Hemagglutinins; Humans; Hypersensitivity, Delayed; Hypoxanthine Phosphoribosyltransferase; Immunoglobulins; Immunologic Deficiency Syndromes; In Vitro Techniques; Lectins; Lesch-Nyhan Syndrome; Lymphocyte Activation; Lymphocytes; Male; Mercaptopurine; Mitogens; Purines; T-Lymphocytes; Thymidine

The recently discovered association of adenosine deaminase (ADA) deficiency and combined immune deficiency (CID) has emphasized the critical role of purine salvage in the function of lymphoid tissue. Known enzymatic properties of ADA are presented. In addition, known phenotypic data and possible genetic mechanisms for the occurrence of ADA deficiency in CID are discussed. A hypothesis based on considerations of known metabolic pathways in human erythrocytes is proposed to account for the selectivity of ADA deficiency for lymphoid tissue. Finally, some inhibitors of ADA are discussed as well as some immunosuppressive agents.

Topics: Adenine; Adenosine Deaminase; Chromosomes, Human, 19-20; Enzyme Inhibitors; Erythrocytes; Humans; Immunogenetics; Immunologic Deficiency Syndromes; Inosine; Isoenzymes; Lesch-Nyhan Syndrome; Liver; Lung; Lymphocytes; Mercaptopurine; Molecular Weight; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Tissue Extracts

Topics: Animals; Antibody-Producing Cells; Antigens; BCG Vaccine; Erythrocytes; Hemolytic Plaque Technique; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Leukemia, Experimental; Male; Mercaptopurine; Mice; Mice, Inbred Strains; Mycobacterium bovis; Time Factors

Topics: Adult; Aged; Antibodies; Antigens; Cyclophosphamide; Cytarabine; Female; Hemocyanins; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Lectins; Leukemia, Myeloid, Acute; Leukocyte Count; Lymphocyte Activation; Lymphocytes; Male; Mercaptopurine; Methotrexate; Prednisone; Prognosis; Remission, Spontaneous; Skin Tests; Thioguanine; Vincristine