mercaptopurine and Lesch-Nyhan-Syndrome

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

Genetic defects in purine metabolism are associated with severe immunodeficiency. Adenosine deaminase deficiency impairs the function of both B- and T-lymphocytes whereas in purine nucleoside (inosine) phosphorylase deficiency there is more severe impairment of T-lymphocyte functions than of B-lymphocyte functions. The relative unimportance of the salvage pathway catalysed by hypoxanthine-guanine phosphoribosyltransferase is shown by the normal responses of T-lymphocytes from patients with the Lesch-Nyhan syndrome to antigenic and mitogenic stimulation. A mild deficiency of B-lymphocyte function is found in these patients. Agents inhibiting the de novo pathway of purine synthesis, including azaserine, 6-mercaptopurine and azathioprine in low doses, block the responses of normal human lymphocytes to mitogenic stimulation. These observations emphasize the importance of the de novo pathway of purine synthesis in lymphocyte responses to antigenic and mitogenic stimulation. There is considerable heterogeneity in the amount of labelled uridine incorporated into human and rat lymphocytes. This does not appear to reflect only a difference between T- and B-lymphocytes

Topics: Adenine Phosphoribosyltransferase; Adenosine Deaminase; Adolescent; Adult; Allopurinol; Azaserine; B-Lymphocytes; Child; Child, Preschool; Humans; Hypoxanthine Phosphoribosyltransferase; Immunoglobulins; Lectins; Lesch-Nyhan Syndrome; Lymphocyte Activation; Male; Mercaptopurine; Mitogens; Phosphoribosyl Pyrophosphate; Purine-Nucleoside Phosphorylase; Purines; RNA; T-Lymphocytes; Thymidine; Uridine

The mixed lymphocyte reaction of Lesch-Nyhan patients (HGPRT deficient) was used to study the immunosuppressive effects of azathioprine and 6-mercaptopurine (6-MP). Mitogen stimulated lymphocytes of these patients are highly resistant to azathioprine and 6-MP. When both stimulator and responder lymphocytes in the MLR were HGPRT deficient, azathioprine (36 microM) was much more inhibitory than 6-MP (100 microM). Azathioprine produced inhibition of 98.2% and 78.5% compared with the values of 63.9% and 30.6% for 6-MP. The difference in inhibitory activity between azathioprine and 6-MP was reduced when normal stimulator lymphocytes were cultured with HGPRT deficient responder lymphocytes in the MLR. These results provide very strong evidence that the nucleotide metabolites of azathioprine and 6-MP are unnecessary for immunosuppression. They also suggest that azathioprine and 6-MP interfere with antigenic triggering of the MLR.

Topics: Adolescent; Azathioprine; Humans; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Lymphocyte Culture Test, Mixed; Lymphocytes; Male; Mercaptopurine

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: Adenine; Adolescent; Aminopterin; Azaguanine; Blood Urea Nitrogen; Carbon Isotopes; Cell Line; Creatinine; Drug Resistance; Electrophoresis, Starch Gel; Erythrocytes; Fibroblasts; Gout; Guanine; Humans; Hypoxanthines; Lesch-Nyhan Syndrome; Male; Mercaptopurine; Pentosyltransferases; Purines; Uric Acid