Proliferation Of Rat Thymocytes Research Articles

IMPACT OF RONCOLEUKIN (RIL-2) ON THE LYMPHOCYTE-TRIGGERING ACTIVITY OF MACROPHAGES AFTER TRAUMATIC BRAIN INJURY IN VARIOUSLY AGED RATS

IL-1β is involved in both brain damage process and the mechanisms of brain regeneration processes. The goal of the present research is to measure the change in the production of lymphocyte-activating factor (LAF) after experimental traumatic injury (TBI) in variously aged rats and evaluate the possibility to correct LAF production with roncoleukin (rIL-2). LAF activity in the supernatants of peritoneal macrophages of injured rats was measured by its ability to have comitogenic effect on the proliferation of rat thymocytes stimulated by suboptimal lectin doses. LAF stimulation index was defined as ratio of stimulated to unstimulated levels of LTF. Results and discussion. The strongest suppression of microphages’ cytokine-producing function was found in older rats after TBI. rIL-2 injection significantly reversed the injuries caused by TBI even in older rats. These data confirm that exogenic IL-2 is able to activate the functional characteristics of innate immunity cells and that is has a normalizing effect on the immune cells of the older animals.

Thiorphan-Induced Survival and Proliferation of Rat Thymocytes by Activation of Akt/Survivin Pathway and Inhibition of Caspase-3 Activity

The activity of substance P (SP) in the rat thymus seems to be tightly controlled by its bioavailability. In this study, we provide evidence for the expression of the SP-degrading enzyme, neutral endopeptidase (NEP)/CD10, by rat thymocyte subsets, and we illustrate its involvement in the in vivo SP/neurokinin-1 receptor (NK(1)R)-mediated regulation of thymocyte survival and proliferation. NEP/CD10 was expressed at both mRNA and protein levels on a substantial portion (45.5%) of CD5(+) thymocytes, namely on the CD4(+)CD8(+) (double positive; DP) and CD4(+) subsets. Continuous administration of thiorphan, a specific NEP/CD10 inhibitor, by means of miniosmotic pumps, enhanced rat thymocyte preprotachykinin-A (PPT-A) and NK(1)R mRNA expression as well as SP and NK(1)R protein levels in an NK(1)R-dependent manner. Thiorphan increased CD10(+)CD4(+) and CD10(+)DP thymocyte numbers, and an NK(1)R antagonist, (S)1-{2-[3(3-4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)-piperidine-3-yl]ethyl}-4-pheny-1-azoniabicyclo[2.2.2]octane, chloride (SR140333), abrogated these stimulatory effects. In addition, the NEP/CD10 inhibitor stimulated interleukin (IL)-2 production, IL-2 receptor alpha chain expression, and concanavalin A-induced proliferation of CD5(+) thymocytes, and it inhibited spontaneous and NK(1)R-dependent thymocyte apoptosis. The thiorphan-protective antiapoptotic and proliferative effects involved the activation of Akt serine-threonine kinase, subsequent up-regulation of survivin mRNA, down-regulation of procaspase-3 mRNA levels, and suppression of caspase-3 activity, which were inhibited by SR140333 and mimicked by exogenous SP administration. Overall, our findings suggest that by controlling SP availability, NEP/CD10 negatively regulates thymocyte homeostasis and development.

In vitro cytostatic and immunomodulatory properties of the medicinal mushroom Lentinula edodes

Lentinula edodes, known as "shiitake" is one of the widely used medicinal mushrooms in the Orient. Antitumour activity of extracts of this mushroom has been widely demonstrated in animals and humans. However, this activity was shown to be host mediated and not by direct cytotoxic activity to cancer cells. This study demonstrates cytotoxic and cell growth inhibitory (cytostatic) effect of aqueous extracts of the mushroom on MCF-7 human breast adenocarcinoma cell line using an MTT cytotoxicity assay. Such effect was demonstrated with fruit body and mycelial extracts, the difference being that there was no significant suppression on normal cells with the latter. Furthermore mycelial extracts did not induce any cytostatic effect in both cancer and normal cell lines based on a DNA synthesis assay. The significant suppression of the proliferation of cancer cells was reflected by the comparatively low IC(50) values and the simultaneous higher respective values on normal fibroblast cells. The immunostimulatory activity of both fruit body and mycelial extracts was tested by the lymphocyte transformation test (LTT), which is based on the capacity of active immunomodulators to augment the proliferative response of rat thymocytes to T mitogens in vitro. Both fruit body and mycelial preparations were able to enhance the proliferation of rat thymocytes directly and act as co-stimulators in the presence of the T-mitogen PHA. Interestingly both extracts, similarly to zymosan showed SI(comit)/SI(mit) ratios of about 2, indicating adjuvant properties. Overall L. edodes aqueous extracts have demonstrated direct inhibition of the proliferation of human breast cancer cells in vitro and immunostimulatory properties in terms of mitogenic and co-mitogenic activity in vitro.

Almond shell xylo-oligosaccharides exhibiting immunostimulatory activity

Partially O-acetylated xylo-oligosaccharides (DXO) isolated from almond shells by autohydrolysis as well as their de-acetylated form (DeXO) were subjected to chemical, molecular, and structural analyses. They represent a mixture of neutral and acidic oligomers and low-molecular weight polymers related to (4- O-methyl- d-glucurono)- d-xylan. DXO and DeXO showed direct mitogenic activity and enhancement of the T-mitogen-induced proliferation of rat thymocytes, indicating the immunostimulatory potential of the almond shell xylo-oligosaccharides.

The role of rat Crry, a complement regulatory protein, in proliferation of thymocytes

In our previous work we showed that 3F10 monoclonal antibody (mAb), which recognizes the rat complement receptor 1-related/gene protein y (Crry), induces homotipic aggregation of thymocytes. In this work we studied the effect of 3F10 mAb on proliferation of rat thymocytes stimulated with concanavalin A (ConA) or by cross-linking the T cell receptor (TCR) by anti-αβTCR mAb (R73), in vitro, and the mechanisms involved in the process. Our results show that 3F10 mAb stimulates proliferation of total thymocytes triggered by suboptimal concentrations of ConA or TCR cross-linking, in a dose-dependent manner. Maximal stimulation was observed using 10 μg/ml and 20 μg/ml of 3F10 mAb, respectively. The 3F10-induced stimulation of thymocytes proliferation in the presence of ConA, that was followed by increased production of interleukin-2 (IL-2), up-regulation of the expression of IL-2 receptor α (IL-2Rα) and was inhibited by anti-CD11a and anti-CD18 mAbs. Purified thymocytes did not respond by proliferation to 3F10 mAb, either alone or in combination with R73 mAb or ConA. Proliferation of these cells was achieved only in the presence of OX-6 + antigen-presenting cells (APC) and additional signals transmitted by TCR or ConA. These results suggest that Crry is involved in the LFA-1 dependent proliferation of thymocytes, a phenomenon that has not been recognized so far.

Neonatal Capsaicin Treatment Affects Rat Thymocyte Proliferation and Cell Death by Modulating Substance P and Neurokinin-1 Receptor Expression

Herein we provide evidence that substance P (SP) and its neurokinin-1 receptor (NK-1R) expressed on thymocytes counteract thymus depletion induced by neonatal capsaicin (CPS) treatment by affecting thymocyte proliferation and apoptotic death. SP administration reversed the CPS-mediated inhibitory effects on the total thymocyte number and subset distribution, namely CD4+ and CD4– CD8– cells, through its interaction with NK-1R as shown by concomitant NK-1R (SR140333) antagonist administration. SP-induced enhancement of thymus cellularity parallels its ability of inhibiting the thymocyte apoptotic program. Indeed, exogenously administered SP completely nullified CPS-induced apoptosis, and SR140333 abrogated the SP-mediated protective effect. SP administration also stimulated concanavalin A (Con A)-induced thymocyte proliferation of CPS-treated rats, completely reversing the CPS-induced inhibition. The SP-mediated stimulation of Con A-induced thymocyte proliferation was NK-1R dependent as shown by concomitant administration of SP and SR140333 to CPS-treated rats. Our results also demonstrate that CPS treatment induces a marked decrease of thymocyte PPT-A mRNA level and endogenous SP content as evaluated by quantitative RT-PCR, in situ hybridization and cytofluorimetric analysis. By contrast, NK-1R mRNA levels were increased in thymocytes from CPS-treated rats. Exogenous SP administration augmented PPT-A, SP and NK-1R thymocyte expression in CPS-treated rats, and this enhancement was antagonized by SR140333 administration. Overall, our results strongly suggest that the immunomodulatory effects of neonatal CPS treatment on rat thymocyte functions are dependent on vanilloid-mediated regulation of SP and NK-1R functional expression by neuronal and immune cells.

Characterization of immunomodulatory polysaccharides from Salvia officinalis L.

Crude polysaccharide fractions, rich mainly in arabinogalactans (A), pectin (B) and glucuronoxylan-related polymers (D), have been obtained from aerial parts of sage ( Salvia officinalis L.) by sequential extraction with various reagents. Arabinogalactans displayed on HPLC a dominance of lower molecular-mass polymers ( M ̄ w <10 ,000), while pectin and glucuronoxylan-related polysaccharides showed predominance of polymers with M ̄ w >50 ,000. Individual polysaccharide fractions were examined for their immunomodulatory activity in the in vitro comitogenic thymocyte test. The polysaccharide fractions tested possessed the capacity to induce rat thymocyte proliferation in the order D>B>A. Besides, fraction D possessed a significant comitogenic effect, and the SI comit/SI mit ratio 3–4 indicates potential adjuvant properties of this glucuronoxylan-rich material.

Modulatory effects of garlic extracts on proliferation of T-lymphocytes in vitro stimulated with concanavalin A.

Different active components from the garlic (Allium sativum) possess immunomodulatory activity both in vitro and in vivo. However, mechanisms of their actions are not sufficiently elucidated. In this study we examined the effects of garlic aqueous extract (GAE) and garlic ethanolic extract (GEE), prepared from two different garlic powder samples, on proliferation of rat thymocytes and splenocytes in culture, stimulated with concanavalin A (Con A). It has been shown that the extracts from both samples significantly modulate lymphocyte proliferation, triggered by this potent T-cell mitogen, depending on the type and dilutions of extracts and concentrations of Con A. The extracts, alone, were not mitogenic for lymphocytes. Generally, higher concentrations of the extracts showed inhibitory effects, whereas lower concentrations significantly augmented proliferation of lymphocytes. The stimulatory effect of GAE was stronger using splenocytes and suboptimal concentrations of Con A as a consequence of increased interleukin 2 (IL-2) production as well as the expression of IL-2 receptor alpha (IL-2Ralpha). The relationship between these two phenomena was demonstrated using neutralizing anti-IL-2Ralpha monoclonal antibody. The inhibitory effect of GAE correlated with a decrease in IL-2 production, but was not followed by down-regulation of IL-2Ralpha expression. The addition of IL-2 almost completely abolished inhibition of lymphocyte proliferation in the presence of higher concentrations of GAE.

Modulatory effect of 7-thia-8-oxoguanosine on proliferation of rat thymocytes in vitro stimulated with concanavalin A

7-thia-8-oxoguanosine (immunosine) is a guanosine analogue showing immunostimulatory activity on different components of the immune system, including B lymphocytes, natural killer cells and macrophages. However, little is known about its effect on T-cell functions. In this work it was demonstrated that immunosine at concentrations between 10 μM and 1 mM stimulated proliferation of rat thymocytes in vitro triggered by suboptimal concentrations of concanavalin A (Con A). The effect correlated with increased interleukin 2 (IL-2) production, upregulation of the IL-2 receptor α (IL-2Rα) expression and decreased apoptosis of thymocytes in comparison to the effect of Con A alone.

Critères prédictifs de la normalisation des chiffres tensionnels après ablation chirurgicale d'un adénome de Conn

Curcumin (diferuoylmethane), the yellow pigment in the rhizome of tumeric (Curcuma longa), an ingredient of curry spice, is known to exhibit a variety of pharmacological effects including antitumor, antiinflammatory, and antiinfectious activities. Although its precise mode of action remains elusive, curcumin has been shown to suppress the activity of the AP-1 transcription factor in cells stimulated to proliferate. In this study, we observed that curcumin (50 μM) inhibited proliferation of rat thymocytes stimulated with concanavalin A [Con A) as well as that of human Jurkat lymphoblastoid cells in the logarithmic growth phase. The pigment also inhibited apoptosis in dexamethasone-treated rat thymocytes and in UV-irradiated Jurkat cells as judged by DNA ladder formation, cellular morphological changes, and flow cytometry analysis. The inhibition of apoptosis by curcumin in rat thymocytes was accompanied by partial suppression of AP-1 activity. Complete suppression of AP-1 activity was observed in Con A-treated, proliferating thymocytes. The capacity of curcumin to inhibit both cell growth and death strongly implies that these two biological processes share a common pathway at some point and that curcumin affects a common step, presumably involving a modulation of the AP-1 transcription factor.

The anti-rat Thy-1.1 monoclonal antibody R2-12C5 recognizing rat, mouse, hamster, and mongolian gerbil Thy-1 antigen had no effect on IL-2 induced rat thymocyte proliferation

The reactivity of MAb R2-12C5 with various rat lymphoid cell populations was defined by immunofluorescence staining following FACScan analysis. R2-12C5 reacted with 94% of rat thymocytes; approximately 85% of Mongolian gerbil, AKR mouse, and hamster thymocytes; 35% to 45% of rat, Mongolian gerbil, AKR mouse, and hamster spleen cells; 30% to 60% of rat, Mongolian gerbil, AKR mouse, and hamster mesenteric lymph node cells; 76% of rat bone marrow cells; 55% to 60% of Mongolian gerbil and hamster bone marrow cells; and 92% of AKR mouse bone marrow cells. Furthermore, R2-12C5 antibody reacted with mouse Thy1.1 gene-transfected mouse B-cell lymphoma K46T13 cells.

Immunoregulatory Activity in Adult Rat Testicular Interstitial Fluid: Relationship with Intratesticular CD8+ Lymphocytes following Treatment with Ethane Dimethane Sulfonate and Testosterone Implants1

Regulation of T-cell traffic and function in the adult rat testis was assessed following treatment with the specific Leydig cell cytoxin, ethane dimethane sulfonate (EDS), and s.c. testosterone implants to prevent Leydig cell recovery. The distribution of T-cell subsets in the testis was determined immunohistochemically using stereological techniques. Testicular T cell-inhibiting activity in the interstitial fluid was measured using a phytohemagglutinin-activated rat thymocyte proliferation bioassay. The mostly cytotoxic CD8+ T-cell subset predominated over the CD4+ (regulatory) T-cell subset in the normal rat testis. Destruction of the Leydig cells caused a rapid preferential increase in testicular CD4+ T cells, which was followed by an increase in both the CD8+ subset and T cell-inhibiting activity in the Leydig cell-deficient testis. After Leydig cell recovery, there was a significant shift toward the CD8+ T-cell subset in the EDS-treated testis but not in the EDS-treated/testosterone-implanted testis. Total T-cell numbers and inhibitory activity in the testis returned to control levels regardless of whether the Leydig cells were allowed to recover. The level of inhibitory activity was closely related to the number of CD8+ T cells in the testis across all experimental groups, but it showed no relationship with pituitary hormones, macrophage numbers, or intratesticular testosterone levels. The data suggest that 1) cytotoxic lymphocytes have a potentially significant role in testicular function and 2) T cell-inhibiting activity in the testis interstitium is not substantially affected by changes in pituitary hormones or Leydig cell function, but appears to be related to local changes in immune activity.

Inhibition of proliferation and apoptosis of human and rat T lymphocytes by curcumin, a curry pigment

Curcumin (diferuoylmethane), the yellow pigment in the rhizome of tumeric ( Curcuma longa), an ingredient of curry spice, is known to exhibit a variety of pharmacological effects including antitumor, antiinflammatory, and antiinfectious activities. Although its precise mode of action remains elusive, curcumin has been shown to suppress the activity of the AP-1 transcription factor in cells stimulated to proliferate. In this study, we observed that curcumin (50 μM) inhibited proliferation of rat thymocytes stimulated with concanavalin A [Con A) as well as that of human Jurkat lymphoblastoid cells in the logarithmic growth phase. The pigment also inhibited apoptosis in dexamethasone-treated rat thymocytes and in UV-irradiated Jurkat cells as judged by DNA ladder formation, cellular morphological changes, and flow cytometry analysis. The inhibition of apoptosis by curcumin in rat thymocytes was accompanied by partial suppression of AP-1 activity. Complete suppression of AP-1 activity was observed in Con A-treated, proliferating thymocytes. The capacity of curcumin to inhibit both cell growth and death strongly implies that these two biological processes share a common pathway at some point and that curcumin affects a common step, presumably involving a modulation of the AP-1 transcription factor.

Immunomodulatory effects of the alkaloid sinomenine in the high responder ACI-to-Lewis cardiac allograft model.

Extracts of the plant Sinomenium acutum have been used safely since ancient times in Chinese medicine for treatment of rheumatic diseases, and the purified alkaloid, sinomenine, was recently shown to have anti-inflammatory and antirheumatic effects. This study describes the effects of sinomenine in the high responder ACI-->Lewis cardiac transplant model in which allograft rejection occurred at 5 days posttransplant. Treatment with sinomenine (15-30 mg/kg/day i.p.) or a subtherapeutic dose of cyclosporine (CsA, 1.5 mg/kg/day, i.m.) prolonged allograft survival only marginally (mean survival of 5.4 and 7.8 days, respectively). In contrast, the combination of sinomenine and CsA had a statistically significant synergistic effect, with a mean survival of 42.2 days (P < 0.001). Allografts harvested at day 5 from recipients treated with either sinomenine or CsA showed dense mononuclear cell infiltrates with widespread subepicardial infarcts, edema, and microvascular platelet and fibrin deposition. Immunohistologic analysis showed that intragraft leukocytes consisted of >75% macrophages with approximately 10-20% T cells and <5% B or NK cells. Mononuclear cell activation was shown by expression of IL-2R (CD25, 10-20%) and labeling for IL-2 (approximately 10%), and IFN-gamma (10-20%), as well as TNF-alpha (>50%) and iNOS (>50%), but only low levels of IL-4 or IL-10 (<5%). Intragraft endothelial cells were activated, as shown by upregulation of MHC class II antigen and ICAM-1 (CD54) compared with only basal levels in normal donors hearts. Combined sinomenine/CsA therapy significantly enhanced graft morphology, resulting in only mild mononuclear cell infiltration, and an absence of infarcts, platelets, or fibrin deposition. Though residual intragraft mononuclear cells at day 5, as in control grafts, consisted primarily of macrophages plus small numbers of IL-2R+ T cells, these cells lacked expression of IL-2, had only low levels of IFN-gamma, but showed dense labeling for IL-4 and IL-10. In addition, TNF-alpha and iNOS were reduced to basal levels and no endothelial cell activation was observed, despite high titers of endothelium-bound IgM, IgG, and C3. Mitogen-induced in vitro proliferation of rat thymocytes was also more effectively decreased by the sinomenine/CsA combination than by either agent alone. These studies demonstrate the therapeutic value of sinomenine in transplantation, and indicate that this agent has novel and interesting antimacrophage, T cell, and endothelial effects that warrant further evaluation.

In vitro effects of retinoid RO 10-9359 on lectin-induced activation and proliferation of T-lymphocytes.

RO 10-9359 has been shown to cause a dose-dependent (0.05-50 micrograms/ml) inhibition of proliferation of rat thymocytes after in vitro activation by PHA and Con A. In experiments designed to dissect the effects of the drug on various aspects of proliferation it was demonstrated that RO 10-9359 did not inhibit IL1 production by macrophages, nor the IL1-dependent events of T-cell activation, i.e. the IL2 production and the acquisition of IL2-receptors. However, the capacity of exogenously supplied IL2 to stimulate the proliferation of T-cells that had previously acquired IL2-receptors was suppressed by RO 10-9359 in a dose-dependent manner. Thus, it appears that retinoid RO 10-9359 does not interfere with the early events of T-cell activation, but inhibits lectin-induced proliferation by affecting the later phase of proliferative activity after T-cell triggering.

Selective effects of human cord serum on distinct events of the lectin-induced activation and proliferation of thymic T-cells

The results of this study demonstrate that human cord serum, but not adult serum, contains a factor(s) which without being by itself mitogenic for unstimulated resting cells, enhances the PHA- and ConA-induced proliferation of rat thymocytes. Dissection of the effects of HCS on the distinct events involved during lectin-induced activation and growth of thymic T cells, revealed the basic mechanisms by which the stimulatory factor(s) exerts its action. HCS does not affect the IL2-dependent proliferation of ConA-blasts derived from thymocytes. Furthermore, it does not act via macrophages but rather directly on thymic T cells by increasing their capacity to proliferate in response to the activating signals delivered by lectins in conjunction with IL1. Thus, HCS enhances the lectin-induced expression of IL2-receptors as evidenced by both increased responsiveness to IL2 and increased capacity to absorb IL2 of HCS-treated thymocytes. On the other side, HCS also enhances the lectin-induced production of IL2 by thymocytes.

DNA content and proliferation of rat thymocytes

Scanning microdensitometric analysis of Feulgen stained thymocytes from rats aged 1 to 71 days revealed the presence of a number of waves of cell proliferation which may correlate with the development of functionally distinct T-cell subpopulations. In addition, considerable numbers of hypodiploid cells were seen. It is tentatively suggested that thymocyte development involves reduction division and replication of the haploid chromosomes so produced, prior to cell proliferation.

Calcium-mediated effects of cyclic GMP on the stimulation of thymocyte proliferation by prostaglandin E 1 .

SummaryLow (10-11 to 10-10M) and high (10-6 to 5 × 10-6M) cyclic GMP concentrations raise the cellular cyclic AMP content and stimulate rat thymocyte proliferation, but intermediate (10-9 to 10-7M) cyclic GMP concentrations have no effect on these activities. The intermediate cyclic GMP concentrations also do not affect the ability of prostaglandin E1 (PGE1) to raise the cellular cyclic AMP concentration and stimulate DNA synthesis. However, depending on the intracellular cyclic AMP content and the extracellular calcium concentration, the intermediate cyclic GMP concentrations can either strongly promote or completely inhibit progression of the PGE1-stimulated, DNA-synthesizing cells into mitosis. It is concluded that calcium mediates the actions of cyclic GMP and an attempt is made to explain the complex actions of these agents on the mitogenic process.

The roles of calcium and cyclic AMP in the stimulatory action of parathyroid hormone on thymic lymphocyte proliferation.

AbstractBoth the parathyroid hormone (PTH) and the calcium ion increase the cellular content of cyclic adenosine 3′,5′‐monophosphate (cyclic AMP), promote the initiation of deoxyribonucleic acid synthesis and stimulate the proliferation of rat thymocytes maintained in vitro. The ability of cyclic AMP to serve as the mediator of the mitogenic actions of both PTH and calcium is established by the fact that cyclic AMP itself stimulates cell proliferation in the absence of PTH and extracellular calcium. Neither PTH nor calcium appear to raise the cellular cyclic AMP level by increasing the nucleotide's synthesis by adenylate cyclase (formerly adenyl cyclase); PTH concentrations as high as 50 μg per ml of medium do not increase the enzyme's activity (in the presence or absence of calcium) and mitogenic calcium concentrations inhibit it. PTH also does not directly affect isolated thymocyte phosphodiesterase, but mitogenic calcium levels inhibit the enzyme's activity. Additional experiments show that it is calcium which raises the cyclic AMP level in cells treated with PTH, and some possible calcium‐mediated mechanisms by which the hormone could elevate the cellular cyclic AMP levels are discussed. Thus, the mitogenic action of PTH is primarily mediated by calcium while cyclic AMP is the ultimate implementor of the hormonal action. However, calcium has a dual role and evidence is presented which indicates that besides raising the cellular cyclic AMP level, it also controls the operation of cyclic AMP's mitogenic end‐reaction.

Cyclic AMP-mediated stimulation by calcium of thymocyte proliferation

Varying the extracellular calcium concentration between 0 and 1.0 mM does not affect the proliferation of rat thymocytes maintained in vitro. However, higher calcium concentrations raise the level of cell proliferation and increase the intracellular concentration of cyclic AMP. Calcium's mitogenic action is inhibited by imidazole, a compound which increases the activity of the cyclic AMP-degrading enzyme phosphodiesterase and thereby also prevents calcium from increasing the cellular cyclic AMP content. Caffeine, which inhibits phosphodiesterase activity, sensitizes thymocytes to the mitogenic action of calcium. Caffeine can also stimulate thymocyte proliferation by itself and, like calcium, causes a significant rise in the cellular cyclic AMP content. Mitogenic levels of calcium, in turn, act like caffeine and reduce the activity of cyclic AMP-phosphodiesterase. These observations combine to suggest that calcium is the physiological equivalent of caffeine and exerts its effect on thymocyte proliferation by reducing the activity of cyclic AMP-phosphodiesterase.