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Biomedical subjects

R E Birch

Publications and source records attributed to R E Birch.

10 recordsLinked to original sources
PubMed1986

Adenosine induced immunosuppression: the role of the adenosine receptor--adenylate cyclase interaction in the alteration of T-lymphocyte surface phenotype and immunoregulatory function.

Adenosine (1 microM at 37 degrees C) rapidly modulates the expression of T-lymphocyte surface antigens (OKT4 and OKT8) and Fc gamma receptors, and increases T-suppressor activity for pokeweed mitogen driven in vitro immunoglobulin synthesis. The adenosine induced loss of OKT4 expressed was maximal within 5 min, while increased OKT8 expression developed more slowly; increased Fc gamma expression was maximal at 30 min after initiation of incubation with adenosine. Adenosine, 2-chloroadenosine and adenosine in the presence of nitrobenzylthioinosine (NBTI) induced the decrease in OKT4 expression. In contrast only adenosine induced the enhancement of OKT8 and Fc gamma receptor expression. Neither 2-chloroadenosine, a poorly transported analog, nor adenosine in the presence of the adenosine transport inhibitor NBTI were capable of enhancing OKT8 or Fc gamma receptor expression. Adenosine was shown to cause a rapid biphasic increase in cAMP, while 2-chloroadenosine and adenosine with NBTI induces a prolonged elevation in cAMP. Similarly isoproteranol which induces a sustained elevation in cAMP suppressed the adenosine induced increases in OKT8 and Fc gamma receptor expression. Incubation of T-helper/inducer lymphocytes with 1 microM adenosine for 30 min at 37 degrees C caused the loss of T-helper function; this loss of T-helper activity has previously been shown to result from the activation of T-suppressor cells. The loss of T-helper function was blocked by the simultaneous addition of isobutylmethylxanthine, an R site adenosine receptor antagonist, or NBTI, an adenosine transport inhibitor. Moreover, 2-chloroadenosine could not induce loss of T-helper function.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1983

Impaired immunoregulation in systemic lupus erythematosus: defective adenosine-induced suppressor T lymphocyte generation.

It is currently unclear whether the suppressor cell dysfunction observed during active systemic lupus erythematosus (SLE) reflects a primary T cell disorder or one that results from immunologic modulation of suppressor T cell activity by autoantibodies. To determine whether the suppressor T cell dysfunction of active SLE is the result of a primary T cell disorder, the model of adenosine-induced immunosuppression was utilized to study the suppressor T cell functions of 12 patients with SLE (seven active SLE, five inactive SLE) and 12 matched healthy controls. T lymphocyte phenotyping was performed by utilizing monoclonal antibodies directed against T cell-specific determinants. Suppressor T cell functions were assessed by two assays in parallel. The first technique tested the capacity of two suppressor T cell subsets (spontaneous suppressors, Ts; adenosine-inducible suppressors, TRA) to inhibit pokeweed mitogen- (PWM) induced B cell differentiation. In the second technique, the ability of enriched T cell preparations to suppress mitogen- and alloantigen-induced proliferation was assayed. It was demonstrated that brief treatment of the control theophylline-resistant T lymphocyte (TR) subset possessing inducer/helper activity with adenosine (10(-5) M, 30 min, 37 degrees C) triggered a rapid shift in phenotype (RFC gamma -, T-4+ leads to RFC gamma +, T-8+) in a proportion of the subset, and the development of radioresistant suppressor function. By contrast, exposure of active SLE TR to adenosine failed to induce either the switch of phenotype or suppressor activity. When compared to controls, both the TS and TRA suppressors failed to inhibit B cell differentiation (TS, p less than 0.001; TRA, p less than 0.001). Moreover, enriched T cell preparations incompletely suppressed the proliferative responses to phytohemagglutinin (p less than 0.003), PWM (p less than 0.0003), or alloantigens (p less than 0.01). During inactive SLE, the T cell responses were usually restored. Treatment of the TR subsets with adenosine induced a switch of phenotype in four of five patients and the subsequent expression of effective suppressor function. We conclude that a) during active SLE, there is impaired suppression of proliferation and B cell differentiation; b) the impaired suppression of B cell differentiation results from abnormal spontaneous (TS) and adenosine-inducible (TRA) suppressor functions; c) the defective generation of suppressor T cell function during active disease results, in part, from a block in the transition from inducer/helper to suppressor cell; and, d) the suppressor T cell dysfunction is reversible with disease remission. The investigation of immunopharmacologic events by using the adenosine-induced immuno-suppression model in T cells from normal donors and SLE patients may provide insights into the molecular basis of disordered immunoregulation in SLE.

Adenosine↗
PubMed1982

Abnormal adenosine-induced immunosuppression and cAMP metabolism in T lymphocytes of patients with systemic lupus erythematosus.

Normal human T lymphocytes incubated with adenosine (10 muM) for 30 min at 37 degrees C show an increase in the percentage of cells expressing receptors for the Fc portion of IgG (RFc(gamma)) and the OKT8 antigen, while the proportion of OKT4(+) cells decreases. These effects occur exclusively in a subset of T cells with theophylline-resistant sheep erythrocyte receptors (T(R) cells) that is enriched for OKT4(+) cells. Untreated normal T(R) cells express helper/inducer cell activity for T-cell-dependent B-cell differentiation, while adenosine-treated T(R) cells suppress B-cell differentiation. In contrast, in T(R) cells isolated from patients with systemic lupus erythematosus (SLE), adenosine fails to induce immunosuppressor activity or to increase the percentage of OKT8(+) and RFc(gamma) (+) cells. In addition, although incubation of normal T(R) cells with adenosine causes a transient increase in cAMP levels (up to 160% of control within 5 min), in SLE T(R) cells, cAMP levels fall by 50% within 10 min. The photoaffinity label 8-azidoadenosine cyclic [(32)P]monophosphate has been used to show that human T lymphocytes have a single cAMP receptor site that appears to be the regulatory subunit of type I protein kinase. In normal T(R) cells, this receptor becomes occupied in response to adenosine. In contrast, in SLE T(R) cells, no change in cAMP receptor occupancy is detected. Although adenosine has a differential effect on normal and SLE T(R) cells, cAMP derivatives that can traverse the cell membrane (8-bromo- and 8-azidoadenosine cyclic monophosphates) induce an increase in the RFc(gamma) (+) cell subset in both normal and SLE T(R) cells. These results suggest that cAMP mediates the effects of adenosine on cell surface markers of T lymphocytes. The lack of an adenosine receptor-coupled adenylate cyclase activity in SLE T(R) cells may account, in part, for their lack of immunosuppressive activity.

Adenosine↗
PubMed1982

Pharmacological modification of immunoregulatory T lymphocytes . II. Modulation of T lymphocyte cell surface characteristics.

Human peripheral blood lymphocytes were fractionated into non-T lymphocyte, T lymphocyte, theophylline resistant (TR) and theophylline sensitive (Ts) T lymphocyte subpopulations. The proportion of cells bearing surface membrane immunoglobulin (sIg), Clq, Ia antigen, beta 2 microglobulin and T lymphocyte specific antigens detected by monoclonal antibodies OKT3, OKT4, OKT5 and OKT8 was studied using immunofluorescent techniques. Incubation of T lymphocytes or TR lymphocytes with adenosine or impromidine, an H2 histamine agonist, under conditions previously shown to increase Fc gamma receptors and radioresistant suppressor cell activity, was found to increase the proportion of cells expressing readily detectable surface beta 2 microglobulin and the antigen detected by OKT8. Cells expressing OKT4 antigen declined and there was no change in OKT3, OKT5, Ia, Clq, sIg or Es receptor expression. These data indicate that the expression of T lymphocyte Fc gamma receptors, beta 2 microglobulin and the antigens detected by the monoclonal antibodies OKT4 and OKT8 are, at least in part, regulated by agents acting upon adenosine and H2 histamine receptors.

Adenosine↗
PubMed1982

Pharmacological modification of immunoregulatory T lymphocytes. I. Effect of adenosine, H1 and H2 histamine agonists upon T lymphocyte regulation of B lymphocyte differentiation in vitro.

Human peripheral blood T lymphocytes were fractionated according to the lability of their sheep red blood cell (E) receptors to theophylline. Theophylline sensitive (Ts) cells function as suppressors of pokeweed mitogen induced B cell differentiation into plasma cells, while theophylline resistant (Tr) cells function as helper/inducer cells in this reaction. The Ts fraction is enriched for cells bearing receptors for the Fc portion of IgG (RFc gamma) while the Tr fraction is depleted of RFc gamma bearing cells. Brief exposure of Tr cells to adenosine or impromidine, an H2 histamine agonist, cause a rapid increase in the number of Tr cells bearing RFc gamma and the development of radioresistant suppressor cell activity. The RFc gamma induced on Tr cells by adenosine or impromidine are more stable in culture than the spontaneously occurring RFc gamma on Ts cells. Ts suppressor activity is radiosensitive and exposure of Ts cells to 2(2-pyridyl)ethylamine, an H1 histamine agonist, results in a marked decrease in RFc gamma on Ts cells as well as loss of Ts suppressor activity. These data indicate that RFc gamma expression and the immunoregulatory function of T lymphocyte subsets may be modified by drugs acting upon adenosine, H1 and H2 histamine receptors.

Adenosine↗
PubMed1982

Cell populations in leucocyte adherence inhibition: requirement for T lymphocytes with IgG Fc receptors.

The subset identity of T lymphocytes participating in the leucocyte adherence inhibition (LAI) reaction was investigated. Humans were immunized with keyhole limpet haemocyanin (KLH) and their cellular immunity was tested by means of the haemocytometer variant of the LAI method. Their lymphocytes were fractionated by rosetting methods employing neuraminidase-treated sheep erythrocytes and IgG- or IgM-coated ox erythrocytes. The T lymphocytes rosetted by IgG-coated ox cells (T gamma) reacted with KLH to give specific LAI reactions. Non-T gamma cells failed to react. The T gamma cells released a lymphokine which caused an LAI reaction of T lymphocytes from non-immunized donors. Immune non-T gamma cells, when incubated with KLH yielded inactive supernates. The normal cells which gave positive LAI responses to the lymphokine also proved to belong exclusively to the T gamma subclass. Cells positively selected with IgM-coated ox cells (T micro) were inactive while the non-T micro lymphocytes behaved like the T gamma cells. It was shown that the activity was confined to the T gamma subset throughout the time course of a primary immune response. Thus, LAI reactivity appears to be a property of a very small subclass of lymphocytes which communicate with each other by means of a soluble factor.

Hemocyanins↗