The effect of the CD28 activation pathway on the immunosuppressive action of cyclosporine.

The effect of the CD28 activation pathway on the immunosuppressive action of CsA was assessed. Human peripheral blood lymphocytes were stimulated with anti-CD3, bryostatin (Bryo) a novel activator of protein kinase C (PKC) and anti-CD28 singly or in combination, to which graded doses of CsA were added to determine relative sensitivity. Proliferation, IL-2 production, and IL-2 receptor expression were assessed and the IC50 determined. Lymphocytes stimulated with Bryo exhibited a marginal proliferative response but expressed the IL-2 receptor despite the presence of CsA. Addition of anti-CD3 or anti-CD28 to Bryo-stimulated lymphocytes promoted a vigorous proliferative response. CsA effectively inhibited the proliferative response and IL-2 production induced with anti-CD3 and Bryo but did not inhibit the response of cells stimulated with anti-CD28 and Bryo. However, II-2 receptor expression in both sets of cultures were comparable due to the induction of IL-2 receptor by Bryo and was not inhibited by CsA. Costimulation of lymphocytes with anti-CD3 plus anti-CD28 resulted in a 2-3-fold enhancement of proliferation compared with lymphocytes stimulated with anti-CD3 alone. Addition of CsA to lymphocytes stimulated with anti-CD3 resulted in the dose-dependent suppression of the proliferative response and IL-2 production (IC50 = 10-25 nM) but less so for IL-2 receptor expression (IC50 = 100-150 nM). In comparison, the proliferative response and IL-2 production elicited by anti-CD3 + anti-CD28 was more resistant to the effects of CsA (IC50 = 100-200 nM). However, IL-2 receptor expression exhibited comparable sensitivity to CsA (IC50 = 100-200 nM) in the presence of anti-CD28. Combination drug:drug studies revealed that CsA and the protein kinase C inhibitor H-7 were additive for both anti-CD3 and anti-CD3 plus anti-CD28 response. On the other hand, the cGMP-dependent protein kinase inhibitor H-8 was synergistic with CsA in inhibiting the response of lymphocytes to anti-CD3 plus anti-CD28 but only additive for responses to anti-CD3. Taken together, these data suggest that CsA inhibits T cell activation at two distinct levels, leading to inhibition of IL-2 production and inhibition of IL-2 receptor expression. Activation of the CD28 pathway partially overcomes the inhibitory activity of CsA on IL-2 production and may be mediated by indirect activation of a cGMP-dependent protein kinase.(ABSTRACT TRUNCATED AT 400 WORDS)     

Differential inhibition of the T cell activation pathway by dexamethasone and cyclosporine

We examined the inhibitory capacity of dexamethasone (DEX) and cyclosporine (CsA) on T cell activation using various accessory cell (AC)-dependent and AC-independent stimuli. We found that CsA strongly inhibited T cell activation in each of the assays used: allogeneic T cell stimulation, phorbol myristate acetate plus concanavalin A, PMA plus anti-CD3 monoclonal antibody (2C11), or PMA plus ionomycin (IONO) T cell activation. DEX was a potent inhibitor of allogeneic stimulation and of the PMA+Con A- or PMA + 2C11-induced T cell stimulation. PMA + IONO stimulation, however, was not affected by DEX. When inhibition occurred, both drugs suppressed [3H]TdR incorporation, IL-2 production, and IL-2 mRNA accumulation, indicating that the sites of interference of these drugs in the T cell activation pathway are located proximal to IL-2 mRNA accumulation. However, the difference in the effects of DEX and CsA in PMA + IONO stimulation suggests that DEX and CsA differentially affect T cell activation.     

西罗莫司和环孢素A对Th17细胞和调节性T淋巴细胞分化影响的比较

目的 比较西罗莫司(SRL)和环孢素A(CsA)对体外诱导CD4+T淋巴细胞向Th17和调节性T淋巴细胞分化的影响.方法 使用抗CD3和抗CD28单克隆抗体(简称抗CD3单抗和抗CD28单抗)刺激CD4+T淋巴细胞,并在培养体系中分别加入转化生长因子β(TGF-β);TGF-β+白细胞介素6(IL-6);TGF-β+IL-6+SRL;TGF-β+IL-6+CsA.72 h后用流式细胞术检测细胞内Foxp3和IL-17的表达水平,观察CD4+T淋巴细胞的分化情况及SRL和CsA对CD4+T淋巴细胞体外分化的影响.结果 在经抗CD3单抗和抗CD28单抗刺激后,TGF-β可诱导Foxp3+细胞(调节性T淋巴细胞,Treg)的增殖与分化,而TGF-β+ID6可诱导Th17细胞的增殖与分化.在培养体系中加人SRL和CsA,均可使Th17细胞的增殖与分化减少;SRL可促进Treg的增殖与分化,而CsA抑制Treg的增殖与分化.结论 SRL可以促进CD4+T淋巴细胞向Treg增殖与分化,而抑制Th17细胞的增殖与分化;CsA既抑制Treg的增殖与分化,又抑制Th17细胞的增殖与分化.     

Pretreatment with glucocorticoids enhances T-cell effector function: possible implication for immune rebound accompanying glucocorticoid withdrawal

Glucocorticoids (GCs) exert their immunosuppressive/antiproliferative effects largely through inhibition of cytokine expression, and paradoxically upregulate the expression of (proinflammatory) cytokine receptors on select nonlymphoid cells. Clinically, withdrawal of GCs was frequently associated with worsening of the outcome of heightened immunity disorders, thereby implicating enhanced cytokine and cytokine receptor expression as a possible consequence of acute/short-term GCs withdrawal. In view of the significance of this complication of GC therapy, we addressed the effect of GC withdrawal on cytokine receptor expression and subsequent T-cell effector function, using the proliferation of human T cells as biological readout. To mimic GC withdrawal, T cells were treated with GCs or controls, stimulated, and incubated for 16-20 h at 37 degrees C, washed, and reactivated for a further 4-48 h. Surface marker expression was assessed by FACS analysis, and proliferation was determined by measuring the cellular uptake of tritiated thymidine. Dexamethasone (DEX) and prednisolone (PRED), in a concentration-dependent manner, inhibited T-cell proliferation induced by anti-CD28 Ab + PMA. However, pretreatment of T cells activated with mitogens, cross-linking antibodies, or PMA + ionomycin ("CD3-bypass" stimulation regimen), but not resting T cells, with DEX or PRED resulted in a marked increase in IL-IR, IL-2R alpha, and IL-6R expression, which was accompanied by a significant enhancement in T-cell proliferation. This effect of GCs was neither stimulus specific nor did it result from alteration in cell viability, and was paralleled by augmentation in cytokine (rIL-2) effects on DEX-pretreated and preactivated T cells. Taken together, our results underline the dual effects of GCs in regulating T-cell activation and cytokine expression. In essence, GCs directly inhibited T-cell proliferation by suppressing cytokine production, and, by enhancing cytokine receptor expression, pretreatment with GCs augmented T-cell proliferation.     

Synergistic inhibitory activities of interleukin-10 and dexamethasone on human CD4+ T cells

BACKGROUND: We have previously demonstrated that interleukin (IL)-10 synergizes with dexamethasone (Dex) in inhibiting proliferation of human T cells, stimulated in an antigen-presenting cell (APC)-dependent manner. Because IL-10 effectively inhibits APC accessory functions, the synergism could have been a result of its effect on APC. We then investigated the effects of Dex and IL-10 on T-cell subpopulations, stimulated in an APC-independent manner. METHODS: CD4 and CD8 T cells were stimulated with anti-CD3, with or without Dex and IL-10, alone or in combination. Proliferation, glucocorticoid (GC) receptor binding, anti-CD3-induced tyrosine phosphorylation, IL-2 production, and expression of IL-2 receptor alpha, beta, and gamma chains were evaluated. The pharmacologic interactions were analyzed using the isobole method. RESULTS: IL-10 synergized with Dex in inhibiting CD4 but not CD8 T-cell proliferation. The synergism was not associated with modifications of GC receptor number or affinity, nor with modifications of anti-CD3-induced tyrosine phosphorylation. IL-10 synergized with Dex in inhibiting IL-2 production and increased Dex inhibitory effect on the expression of the IL-2 receptor alpha chain, which is up-regulated by CD3 stimulation and IL-2. Only Dex inhibited the beta and gamma chain expression, which, interestingly, is not up-regulated by IL-2. IL-2, as well as IL-7 and IL-15, reversed the effects of IL-10 but not those of Dex. CONCLUSIONS: IL-10 synergizes with Dex in inhibiting CD4 T-cell proliferation. Its synergizing effect is mediated by the inhibition of IL-2 production. Dex exerts additional activities, such as the inhibition of beta and gamma chain expression. Therefore, IL-10 could be useful for the enhancement of GC-based immunosuppressive therapies.     

国产免疫抑制剂F904对T细胞激活的抑制及IL—2的调节作用

通过将Ｆ９０４对人外周血单个核细胞体外作用的实验研究，对Ｆ９０４的免疫抑制作用及其机制进行了初步的探讨。结果表明：（１）Ｆ９０４能显著抑制植物血凝素诱导的Ｔ细胞增殖 反应；（２）Ｆ９０４对ＰＨＡ激活的Ｔ细胞表面ＩＬ－２Ｒ的表达呈强烈的抑制作用；     

Baohuoside-1, a novel immunosuppressive molecule, inhibits lymphocyte activation in vitro and in vivo

BACKGROUND: We evaluated the in vitro and in vivo immunosuppressive effects of baohuoside-1 (B1), a novel flavonoid isolated from Epimedium davidii. METHODS: Proliferation assay was used to determine the antiproliferative properties on T-cell and B-cell proliferation. Flow cytometry analysis was applied to detect changes of phenotypes on activated cells. RESULTS: B1 inhibits the lymphocyte proliferation activated by polyclonal mitogens and mixed lymphocyte reaction with a 50% inhibitory concentration of low micromolar concentration. Also, B1 suppressed T-cell activation in T cell receptor/CD3-mediated signaling pathways in a dose- and time-dependent manner. The suppression of B1 was not simply a result of a toxic effect and was recovered by withdrawing the drug. B1 down-regulated the expression of some phenotype molecules. In Ca(2+)-independent or -dependent antigen stimulation, although B1 had different inhibitive patterns on CD69 expression stimulated by phorbol 12-myristate 13-acetate (PMA) or Ca2+ ionophore, it inhibited T-cell proliferation induced by CD3/CD28 or PMA/ionomycin and partially blocked that induced by PMA/CD28. Interestingly, an additive inhibition between B1 and tacrolimus (FK506) was found in the CD69 expression stimulated by PMA/CD28 and PMA/ionomycin. Similarly, this immunosuppression by combination therapy was observed in a heart transplantation model in vivo and might act through an immunosuppressive mechanism different from FK506. CONCLUSIONS: B1, whose mechanism of action is not similar to that of FK506, has selectively immunosuppressive effects on T-cell and B-cell activation in vitro and effectively prevents rat heart allograft rejection in vivo.     

Plant alkaloid tetrandrine and its analog block CD28-costimulated activities of human peripheral blood T cells: potential immunosuppressants in transplantation immunology

BACKGROUND: T lymphocyte activation mediated by CD28 costimulation plays a critical role in graft rejection. Plant alkaloid tetrandrine, purified from a Chinese antirheumatic herb, is a potent immunosuppressant. Here, we examined its effects on several CD28-costimulated T-cell activities. In addition, such effects were readily compared with the effects of three tetrandrine analogs. METHODS: T lymphocytes were purified from whole blood by negative selection. The stimuli that mimic CD28 costimulation included both anti-CD3 + anti-CD28 monoclonal antibody and PMA+anti-CD28 monoclonal antibody. The determination of CD28-costimulated cell proliferation was performed by tritium uptake, cytokine production by ELISA, cell surface interleukin 2Ra and CD69 expression by flow cytometry, and mixed leukocyte reaction by tritium uptake. Drug cytotoxicity was determined by trypan blue exclusion, propidium iodide staining, and MTT colorimetric assays. RESULTS: Tetrandrine inhibited CD28-costimulated T-cell proliferation and cytokine production through a mechanism different from that of cyclosporine. In addition, tetrandrine down-regulated both T helper 1 and T helper 2 cytokine production in CD4+ and CD8+ T-cell subpopulations. By examining cytokine production and T-cell activation marker expression, we further demonstrated that, among tetrandrine and its analogs tested, dauricine was the most potent suppressor of CD28-costimulated T-cell activities. Furthermore, the different immunosuppressive activities of these compounds were not associated with their cytotoxic capacities. Finally, the unparalleled inhibitory potency of dauricine on both mixed leukocyte reaction and CD28-costimulated T-cell proliferation suggests that dauricine preferentially targeted CD28-costimulated T-cell activities. CONCLUSIONS: This is the first report to show that tetrandrine and its analogs potently inhibited both PMA+CD28-costimulated and CD3 + CD28-costimulated activation of human peripheral blood T cells. Based upon their structural similarity and different immunosuppressive potency, these in vitro data also provide very useful information for further identification and development of more potent and less toxic immunosuppressants to achieve transplantation success.     

环孢素A对T细胞活化CD28通路的影响

Ｔ细胞需两种以上刺激信号才能充分活化。环孢素Ａ通过阻断ＣＤ３经通路而产生免疫抑制效应，本文研究ＣｓＡ对ＣＤ２８活化通路的影响。研究发现以抗ＣＤ２单抗和抗ＣＤ２８单抗共刺激后，淋巴细胞增殖比以ＣＤ３单抗单独刺激时显著增强，且对ＣｓＡ不敏感，ＩＤ５０较单独刺激时高４－５倍，研究表明．：ＣＤ２８通路能提供共刺激信号，使ＴＸ以分活化增殖，并且这一活化通路能对ＣｓＡ产生抵抗 。     

A comparison of the inhibitory effects of immunosuppressive agents cyclosporine, tetranactin, and didemnin B on human T cell responses in vitro.

The agents cyclosporine, tetranactin (TN), and didemnin B (DB) were compared for their ability to inhibit proliferative human T cell responses in vitro, using anti-CD3, PHA, alloantigen, or tetanus toxoid as stimuli and using monocytes or Langerhans cells as antigen-presenting cells/accessory cells (APC/AC). We found that all three agents suppressed T cell activation in a dose-dependent fashion, irrespective of the stimulus of APC/AC type used. Both T cells and APC/AC were affected by the drugs. DB appeared to be the most potent suppressive drug (IC50 = 1-4 ng/ml), whereas CsA and TN exerted approximately similar potency (IC50 = 50-60 ng/ml). Remarkably however, DB was toxic at a concentration of 10 ng/ml, which is quite close to the inhibition-inducing dose. No toxicity was observed with CsA and TN at doses up to 5000 ng/ml. The agents TN and DB could interrupt ongoing T cell responses and could block responsiveness to exogenous recombinant IL-2. Expression of IL-2 receptors was slightly inhibited by all three drugs. Expression of MHC class II molecule HLA-D and of adhesion molecules LFA-1, LFA-3, and ICAM-1 was clearly reduced by DB, giving an explanation for the observed inhibition of cluster formation between T cells and APC/AC. Except for a slight reduction of LFA-3 by TN, CsA and TN did not affect the expression of any of these cell surface markers or the formation of clusters. Differences in the effects of CsA, TN, and DB on immune responses in vitro and on the phenotype of T cells and APC/AC suggest that these immunosuppressive drugs have different inhibitory mechanisms.     

赛斯平免疫抑制作用机理的探讨

通过赛斯平对人对周血单个核细胞体外作用的研究，探讨赛斯平的免疫抑制作用及其机理。结果表明，赛斯平能显著抑制植物血凝素（ＰＨＡ）诱导的Ｔ淋巴细胞增殖反应，抑制作用主要发生在早期，而且抑制强度随药物浓度增加而增强，赛期平对ＰＨＡ激活的Ｔ淋巴细胞表面白细胞介素２受体的表达呈强烈的抑制作用（Ｐ〈０．００１）。结果提示赛斯平能显著地抑制淋巴细胞的增殖及白细胞介素２受体的表达，具有满意的免疫抑制效果。     

Differential regulation by dexamethasone and cyclosporine of human T cells activated by various stimuli.

Calcium ionophores such as ionomycin (IONO), CD3 antibody (CD3), or CD28 antibody (CD28) have been shown to stimulate T cells in a quite different fashion. However, each stimulator induces full activation of resting T cells in the presence of phorbol myristate acetate. Human T cells were activated with PMA + CD3, PMA + IONO, or PMA + CD28 and the inhibitory effects of dexamethasone (DEX) and cyclosporine were examined on [3H]-TdR incorporation, IL-2 production, and IL-2 receptor expression. Three inhibition patterns emerged: PMA + CD3 stimulation was DEX-sensitive and CsA-sensitive, PMA + IONO stimulation was CsA-sensitive but DEX-resistant, PMA + CD28 stimulation was DEX-sensitive but CsA-resistant. Although the degree of inhibition by DEX and CsA was different in [3H] TdR incorporation, IL-2 production, and IL-2 receptor expression assays, the inhibitory pattern of these drugs was similar in each of the assays, indicating that human T cell activation is differentially regulated by DEX and CsA depending on the stimulator.     

Modulation of IFN-gamma-induced immunogenicity by phosphatidylethanolamine-linked hyaluronic acid

BACKGROUND: The present study was conducted to examine the possibility of modulating interferon (IFN-gamma)-induced immunogenicity by a novel compound that is composed of a PLA2 inhibitor linked to hyaluronic acid (HYPE). METHODS: HYPE was tested for its effect on IFN-gamma-induced expression of MHC class I, class II, and intercellular adhesion molecule (ICAM-1) in cultured endothelial and renal proximal tubular cells by flow cytometric analysis (FACS) as well as its ability to influence T cell activation in mixed lymphocyte reaction (MLR) or after mitogen stimulation. RESULTS: In FACS, a profound inhibition in MHC class I and ICAM-1 staining was observed in stimulated or unstimulated cells that were incubated with HYPE. This was not due to down-regulation of antigen expression and only occurred when monoclonal antibodies, but not when polyclonal antibodies, were used. HYPE inhibited the induction of MHC class II in both cell types after IFN-gamma stimulation in a dose-dependent manner. Moreover, the induction of class II transactivator (CIITA) was completely inhibited under these conditions, most likely because it blocked the binding of IFN-gamma to the cell membrane. Addition of HYPE to MLR inhibited the proliferation of T cells and the secretion of interleukin (IL)-2, IFN-gamma, and IL-10. This was not observed when HYPE was added together with anti-CD3 or phytohemagglutinin (PHA). CONCLUSION: Our study provides experimental evidence that HYPE has immunosuppressive features. This makes the compound an interesting candidate as an immunosuppressive drug, not only in organ transplantation, but also in diseases where IFN-gamma is overexpressed.     

Inhibition of human monocyte antigen presentation, but not HLA-DR expression, by cyclosporine

The effects of cyclosporine (CsA) on antigen-dependent human T cell proliferation have been studied using tetanus toxoid as the antigen. CsA significantly inhibited antigen-dependent T cell proliferation at concentrations as low as 0.1 microgram/ml. In dissecting this system we found that preexposure of separated monocytes to CsA during the period of antigen processing led to a marked inhibition of proliferation of T cells added subsequently to the monocytes. We investigated whether this suppressive effect on monocyte antigen presentation was related to monocyte HLA-DR expression, interleukin 1 (IL-1) production, or prostaglandin (PG) secretion. None of these functions seemed to be affected by CsA. In particular, human monocyte HLA-DR expression was not inhibited by CsA, even at concentration of 10 micrograms/ml. The addition of exogenous IL-1 or indomethacin did not reverse the inhibitory effects of CsA. These experiments demonstrate that CsA inhibits antigen-dependent human T cell proliferation, at least in part by acting directly on human monocytes to inhibit antigen presentation. The mechanism of action seems to be independent of IL-1 production, PG secretion, and HLA-DR expression.     

Similar effects of cyclosporine and verapamil on lymphokine, interleukin 2 receptor, and proto-oncogene expression

Since calcium channel blocking agents and CsA exert an antiproliferative effect upon T cell mitogenesis, we have compared and characterized their immunosuppressive properties at the level of gene activation. Verapamil (greater than or equal to 30 microM), which blocks T cell mitogenesis and a rise in cytosolic calcium, was added to cultures of peripheral blood mononuclear cells stimulated with phytohemagglutinin (5 micrograms/ml) and phorbol myristate acetate (5 ng/ml). Northern blot analysis was performed using cDNA probes for the p55 interleukin 2 receptor (Tac; IL-2R), interleukin 2 and c-myc at 20 hr of culture. Accumulation of IL-2 encoding mRNA within the cytoplasm was completely abrogated by verapamil. However, IL-2R and c-myc encoding mRNA were clearly detectable in verapamil-treated cell cultures. Surface expression of the Tac protein in mitogen-activated T cells was also not blocked by verapamil as shown by FACS analysis. In companion experiments with CsA, verapamil only partially inhibits the intracellular processes leading to T cell activation. A calcium-independent pathway may exist for the expression of IL-2R and c-myc, while an increase of intracellular Ca2+ may provide the additional signal for IL-2 gene expression. Although the in vitro concentrations of verapamil used in these experiments are in excess of common clinically therapeutic levels, the results help clarify the mode of CsA action and may provide a new tool to dissect the early events of T cell activation.     

The effects of immunosuppressive agents on in vitro production of human immunoglobulins.

We have evaluated the effects of CsA, methylprednisolone (MP), 6-mercaptopurine (6-MP), and FK506 on T cell-dependent and T cell-independent immunoglobulin production. FK506 and 6-MP were potent inhibitors of IgG and IgM production by PWM-stimulated peripheral blood mononuclear cells, which depend on the presence of T cells. CsA was less effective in this system and MP actually enhanced IgG and IgM production. In order to assess the direct effects of these various immunosuppressive agents on B cells, we utilized human B cell lines representing different stages of B cell differentiation. The B cell lines CESS and SKW6.4 exhibit increased production of IgG and IgM, respectively, in response to interleukin-6. These cells represent activated, but not fully differentiated, B cells. CsA inhibited IL-6-induced IgG production by CESS cells by 64% at 100 ng/ml and 6-MP inhibited this response by 82% at 250 ng/ml. Neither CsA nor 6-MP effectively inhibited IL-6-induced IgM production by SKW6.4 cells. MP at 250 ng/ml inhibited IL-6-induced IgG production by 89%, but enhanced IL-6-induced IgM production more than two-fold. FK506 did not inhibit IL-6-induced IgG or IgM production, suggesting that it has no direct effect on the ability of B cells to respond to this differentiation factor. These experiments clearly demonstrate that CsA, MP and 6-MP have direct inhibitory effects on the response of human B cells to IL-6. In contrast, FK506 has no direct effect on these B cells lines, but is more potent than the other agents at inhibiting T cell-dependent immunoglobulin production.     

Human T cell responses to human and porcine endothelial cells are highly sensitive to cyclosporin A and FK506 in vitro

BACKGROUND: Human T cells proliferate in response to both human umbilical vein endothelial cells (HUVEC) and porcine aortic endothelial cells (PAEC) via the second signals LFA-3/CD2 and B7-2 (CD86), respectively. Previous studies have shown that stimulation of T cells via CD28 or phorbol myristate acetate (PMA) activation is highly resistant to inhibition by cyclosporine A (CsA) and tacrolimus (FK506), as is the response of T cells to phytohemmaglutinin in the presence of endothelial cells. We have investigated the inhibitory effects of CsA and FK506 on the direct response of human CD4+ T cells to HUVEC and PAEC and the effect of adding B7-1 transfectants. METHODS: T cell proliferation, interleukin-2 release bioassays and a multiple cytokine bioassay employing the TF-1 cell line were used as indicators of T cell responses to HUVEC and PAEC either in the presence or absence of CsA and FK506. In some experiments, B7-1 transfectants were also added. RESULTS: Proliferative responses and interleukin-2 release were highly sensitive to CsA, the ID50 being significantly less for HUVEC (6.5 ng/ml) than PAEC (15 ng/ml). The ID50 of CsA for the mixed lymphocyte response (MLR) was similar to PAEC (18.6 ng/ml), all these values being significantly less than the T cell activation by phytohemmaglutinin (PHA) (227 ng/ml). Addition of B7-1 transfectants significantly increased interleukin-2 production by T cells/HUVEC and resistance to CsA was greatly increased to an ID50 of > 1000 ng/ml. In contrast, addition of B7-1 transfectants to T cells/PAEC had no effect either on T cell proliferation, IL-2 production, or CsA resistance. Similar results were obtained with FK506. Using the TF-1 cell line, it was determined that cytokines other than IL-2 are released during CD4+ T cell/EC interactions, with similar sensitivity to CsA and FK506. CONCLUSIONS: It is concluded that both allogeneic and xenogeneic T cell/endothelial responses should be inhibited by therapeutic levels of CsA in vivo, assuming the absence of trans-stimulation by B7 molecules.     

Evidence of impaired T cell function in hemodialysis patients: potential role for secondary hyperparathyroidism

Previous studies in our laboratory showed that the T cell is a target for parathyroid hormone (PTH) action. It is theoretically possible, therefore, that chronic exposure of the T cells to high blood levels of PTH in patients with chronic renal failure may adversely affect T cell function. We examined in both normal subjects and dialysis patients several aspects of T cell function, including (1) T cell proliferation in response to phytohemagglutinin (PHA) mitogen with and without PTH and with and without exogenous interleukin 2 (IL-2); (2) the IL-2 production induced by PHA with and without PTH, and (3) resting levels of cytosolic calcium--[Ca2+]i--and the increment in [Ca2+]i in response to anti-CD3 antibody. Although PHA significantly (p less than 0.01) stimulated proliferation of T cells from both normal subjects and dialysis patients, the magnitude of the stimulation was significantly (p less than 0.01) smaller in the latter group. In both normal subjects and dialysis patients, exogenous IL-2 alone stimulated T cell proliferation, and the magnitude of the stimulation was similar to that produced by PHA. Also, IL-2 augmented PHA-induced proliferation of T cells from normal subjects, but failed to do so in T cells from dialysis patients. PHA did not augment IL-2 production by T cells from dialysis patients, and PTH did not correct this defect. The resting levels of [Ca2+]i in T cells from dialysis patients were significantly (p less than 0.01) higher, and the increments in [Ca2+]i in response to anti-CD3 antibody were significantly (p less than 0.01) lower than in T cells from normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)