Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory

BACKGROUND & AIMS: Autoreactive T cells that proliferate in response to autoantigens are found in both autoimmune disease and controls but have important qualitative differences in relative activation states, costimulation signal requirements, and pathogenetic significance. Understanding the mechanism for activation of autoreactive T cells will be critical in the treatment of autoimmune diseases. METHODS: To understand the differences between autoreactive T cells in primary biliary cirrhosis (PBC) versus controls, we have developed autoreactive T-cell clones (TCCs) from patients with PBC and healthy controls and have used a peptide corresponding to the CD4 major autoepitope to define the relative proliferative and cytokine response. RESULTS: Using an enzyme-linked immunosorbent spot assay, peripheral blood mononuclear cells (PBMCs) from PBC, but not from controls, produce interferon (IFN)-gamma regardless of whether costimulation-competent or -incompetent antigen-presenting cells (APC) were used. In contrast, a significant number of IFN-gamma-producing cells were found in PBMCs from controls but only if costimulation-competent PBMCs presented an autoantigenic peptide. In addition, costimulation-dependent autoreactive TCCs became anergic after a single round of stimulation in the presence of APC that did not provide a costimulatory signal, whereas some costimulation-independent autoreactive TCCs required repeated stimulation to become anergic and the others did not become anergic. Finally, anergic TCCs produced interleukin-10, but no IFN-gamma, and exhibited regulatory functions in an antigen-dependent, cell contact-independent, and partially interleukin-10-mediated manner. CONCLUSIONS: These data relate specifically to the functional characteristics of autoreactive T cells in PBC but are also generically important for understanding the mechanisms for generating pathogenetic autoreactive T cells.     

Distinct costimulation dependent and independent autoreactive T-cell clones in primary biliary cirrhosis

BACKGROUND & AIMS: Previous work has suggested that CD4+ CD28- or costimulation-independent T cells are increased in autoimmune diseases. In this study, we compared frequency and qualitative characteristics of autoreactive costimulation-independent or CD4+ CD28- T cells in primary biliary cirrhosis (PBC) by taking advantage of the well-defined immunodominant autoepitope of the E2 component of pyruvate dehydrogenase (PDC-E2). METHODS: We determined the frequency of costimulation-independent autoreactive T cells that respond to PDC-E2 163-176 and the frequency of CD4+ CD28- T cells. Finally, we determined the role of biliary epithelial cells (BEC) as both an antigen-presenting cell or, alternatively, as a target cell for T-cell-mediated cytotoxicity. RESULTS: The precursor frequency of costimulation-independent CD4+ T cells that respond to PDC-E2 163-176 and the frequency of CD4+ CD28- T cells were dramatically elevated in PBC. Furthermore, 2 types of T-cell clones that respond to PDC-E2 163-176 emerged from this study. One type was costimulation dependent and the other costimulation independent. Both types of clones lyse BEC in a similar effector target (E/T) ratio distribution. However, BEC did not help the proliferation of any T-cell clones. Furthermore, costimulation-independent T-cell clones do not become anergic by BEC. CONCLUSIONS: In PBC, costimulation-independent autoreactive T cells, which do not become anergic, increase and maintain the autoimmune response. In controls, although autoantigens are expressed on BEC and autoantigen-reactive T cells exist around BEC, autoantigen-reactive T cells are costimulation dependent and will become anergic and maintain peripheral tolerance.     

Ursodeoxycholic acid reduces CpG-induced IgM production in patients with primary biliary cirrhosis

Aim:  Ursodeoxycholic acid (UDCA) treatment reduces IgM serum levels in patients with primary biliary cirrhosis (PBC) without affecting serum antimitochondrial antibody (AMA) titers. We previously reported that PBC-associated hyper-IgM is secondary to a disease-specific hyperproduction following bacterial stimulation by B cells.
Methods:  We isolated peripheral blood mononuclear cells (PBMC) from patients with PBC and controls and evaluated whether bacterial CpG challenge in the presence of UDCA at concentrations consistent with those achieved in treated patients led to changes in total IgM, IgG-AMA, and IgM-AMA production. Further, p65 phosphorylation and CD38 cell expression were analyzed as measures of activation of the NF-kB signaling pathway and B cell subsets, respectively.
Results:  UDCA significantly reduced CpG-induced total IgM and IgM-AMA production, but had no impact on IgG-AMA production. UDCA also significantly reduced the activation ofnaïve and IgM memory, but not IgG memory, B cells, as represented by CD38 expression levels. Further, p65 phosphorylation was significantly reduced in the presence of UDCA.
Conclusion:  UDCA reduces total and IgM-AMA production in PBMC from patients with PBC by downregulating B cell activation and NF-kB signaling. These data ultimately suggest novel mechanisms of action for UDCA in chronic autoimmune cholestasis.     

原发性胆汁性肝硬化患者外周血单个核细胞Toll样受体表达与调节性T细胞相关性分析

目的 探讨原发性胆汁性肝硬化(PBC)患者外周血单个核细胞(PBMC)Toll样受体2、4、9(TLR2,TLR4,TLR9)表达及PBMC中CD4+ CD25+调节性T细胞(Tregs)特点和影响因素.方法 采用流式细胞术检测PBC患者(52例)和健康对照者(22例)外周血PBMC中TLR2、4、9阳性细胞及Tregs比例,比较其在PBC患者和健康对照者中的差别并分析TLR与Tregs相关性.结果 PBC患者Tregs比例低于健康对照者[(1.53+1.33)vs(4.42±1.43),P＜0.0001],TLR4阳性细胞比例高于健康对照者[(36.95±3.53)vs(32.84±8.06),P=0.003];PBC患者Tregs比例与TLR9阳性细胞比例呈负相关(R2 =0.115,P=0.016),健康对照者Tregs比例与TLR2,4和TLR2,4,9联合表达阳性细胞比例呈负相关(R2=0.326,P=0.007;R2 =0.226,P=0.034).结论 PBC患者外周血PBMC中Tregs比例降低,TLR4表达升高,可能受肝硬化失代偿期腹腔感染的影响.     

Interleukin 2 production, not the pattern of early T-cell antigen receptor-dependent tyrosine phosphorylation, controls anergy induction by both agonists and partial agonists.

Full activation of T cells requires signaling through the T-cell antigen receptor (TCR) and additional surface molecules interacting with ligands on the antigen-presenting cell. TCR recognition of agonist ligands in the absence of accessory signals frequently results in the induction of a state of unresponsiveness termed anergy. However, even in the presence of costimulation, anergy can be induced by TCR partial agonists. The unique pattern of early receptor-induced tyrosine phosphorylation events induced by partial agonists has led to the hypothesis that altered TCR signaling is directly responsible for the development of anergy. Here we show that anergy induction is neither correlated with nor irreversibly determined by the pattern of early TCR-induced phosphorylation. Rather, it appears to result from the absence of downstream events related to interleukin 2 receptor occupancy and/or cell division. This implies that the anergic state can be manipulated independently of the precise pattern of early biochemical changes following TCR occupancy, a finding with implications for understanding the induction of self-tolerance and the use of partial agonist ligands in the treatment of autoimmune diseases.     

Effect of pyruvate dehydrogenase on production of interleukin-6 in peripheral blood mononuclear cells from patients with primary biliary cirrhosis

We investigated the effect of pyruvate dehydrogenase (PDH), a mitochondrial autoantigen, on the production of interleukin-6 (IL-6) by peripheral blood mononuclear cells (PBMC) from nine patients with primary biliary cirrhosis (PBC) and nine patients with other chronic liver disease (CLD) as a control. IL-6 activity was measured by the bioassay using MH-60 BSF2 cells. The mean level of spontaneous secretion of IL-6 from PBMC of PBC patients was significantly (P < 0.01) higher than that of CLD patients. In addition, the level of IL-6 production by PBMC of PBC patients with stimulation of PDH was significantly higher (P < 0.01) than that of CLD patients. On the other hand, the stimulation of PBMC from PBC and CLD patients by pokeweed mitogen (PWM) enhanced the IL-6 production. However, there was no significant difference in the levels of IL-6 produced by PBMC with stimulation of PWM + PDH between PBC and CLD. These findings suggest that PDH is involved in the production of large amounts of IgM and autoantibodies in PBC, by stimulating the production of IL-6 from mononuclear cells.     

Recurrence of primary biliary cirrhosis and development of autoimmune hepatitis after liver transplant: A blind histologic study

Aim:  This long-term study aimed to evaluate recurrence and evolution of primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT).
Methods:  We reviewed "blindly" allograft biopsy specimens of women who underwent transplantation for PBC ( n  = 84), and women who received a transplant for chronic hepatitis C virus infection (CHCV ) ( n  = 108). All needle liver biopsy specimens obtained more than 6 months post-OLT were examined, including 83 specimens from 44 PBC patients and 152 specimens from 58 CHCV patients.
Results:  Granulomatous destructive cholangitis was found in five biopsies from four PBC patients ( P  = 0.0048). Non-necrotizing epithelioid cell granulomas were present in four biopsies from four PBC patients, and in two biopsies from one CHCV patient. Piecemeal necrosis ( P  = 0.0002), lobular necroinflammatory activity ( P  < 0.0001), steatosis ( P  < 0.0001) and fibrosis ( P  < 0.0001) were more prevalent in CHCV patients than PBC patients. Four PBC patients developed histologic evidence of autoimmune hepatitis (AIH), at a mean time of 3.66 years post-OLT. One of these patients had histologic features of AIH/PBC overlap syndrome. All four patients developed bridging fibrosis ( n  = 2) or cirrhosis ( n  = 2). No other PBC patient had evidence of cirrhosis after OLT.
Conclusions:  Histologic findings indicative of recurrent PBC were present in 15.9% of the PBC patients undergoing biopsy in this series. However, this group of patients did not suffer significant bile duct loss or fibrosis, as compared to the control group, suggesting that recurrent PBC is a mild or slowly progressive disease. Histologic evidence of AIH was observed in allograft biopsies of some PBC patients.     

Abnormalities of mononuclear cell regulation in vitro in primary biliary cirrhosis1

ABSTRACT— In primary biliary cirrhosis (PBC) enhanced lymphocyte cytotoxicity, disruption by mononuclear cells of intrahepatic bile ducts, as well as high levels of circulating autoantibodies, immunoglobulins and immune complexes are found. These observations suggest the presence in PBC of defective regulation of immune functions. To evaluate immune regulation of T-cell and B-cell function in PBC, we measured the capability of suppressor cells generated by concanavalin A (Con A) from peripheral blood mononuclear cells (PBMC) to inhibit allogeneic T-cell proliferative responses as well as B-cell immunoglobulin synthesis in vitro. The inhibitory effect of Con A-induced suppressor cells on T-cell proliferation was significantly reduced in PBC patients compared to controls. This immunoregulatory defect did not correlate with indicators of disease activity and was not seen in patients with chronic extrahepatic biliary obstruction. In contrast, Con A-induced suppressor cells from PBC patients inhibited in vitro IgG and IgM synthesis normally. Finding that the potential to generate suppressor cell activity of B-cell immunoglobulin synthesis was preserved in PBC, we explored other mechanisms for elevated globulins in this disease. Comparing in vitro immunoglobulin synthesis by unstimulated and pokeweed mitogen-stimulated PBMC from PBC patients and controls, we found that baseline IgG synthesis in vitro was normal but baseline IgM synthesis significantly depressed in PBC. On the other hand, whereas PBMC from PBC patients responded normally to pokeweed mitogen stimulation of IgM synthesis, the same PBMC were refractory to pokeweed mitogen stimulation of IgG synthesis in vitro. These studies suggest that in PBC there is a dissociation between inducible suppressor cell activity of T-cell function, which is impaired, and inducible suppressor cell activity of B-cell immunoglobulin synthesis, which is preserved. Whereas a defect in regulation of cellular immune function may provide a permissive environment for initiation or perpetuation of cell-mediated autoimmune hepatobiliary injury in PBC, our studies failed to identify an extrinsic immunoregulatory defect to account for humoral immune aberrations, which may result, instead, from altered responsiveness intrinsic to B-cell progeny.     

Autoantibody IgG subclasses to recombinant antigens and the role of bacterial stimuli in primary biliary cirrhosis

Aim:  Serum antimitochondrial antibody (AMA) of the IgG2 and IgG3 subclasses has been reported to be predominant in patients with primary biliary cirrhosis from developed countries. No data are available as to the significance of AMA subtypes in Japanese primary biliary cirrhosis (PBC) patients who have previously manifested unique serological features, nor it is known whether AMA subclasses are influenced by bacterial stimuli, as suggested by the molecular theory of PBC. We undertook a three-step study to address these questions.
Methods:  First, Japanese PBC sera were tested using the established triple recombinant antigen (pML-MIT3) to find AMA subclass distribution. Second, we used the three recombinant mitochondrial antigens in PBC sera of Japanese and USA patients to explore the ethnic difference. Third, we used CpG oligodeoxynucleotides and a B cell mitogen to challenge ex vivo peripheral leukocytes from indirect immunofluorescence (IIF)-AMA-positive patients with Japanese PBC.
Results:  We detected most frequently IgG2-AMA followed by IgG3-AMA, with the latter being more common in IIF-AMA-positive cases, and demonstrated that the IgG3 reactivity against the dominant antigen was significantly higher in PBC sera from the USA. We determined that the bacterial stimulus was superior to the mitogen at inducing a predominant production of IgG2-AMA and CD20+ B cell activation.
Conclusion:  Our data cumulatively supported the hypothesis that IgG2 AMA subtypes are predominant in PBC and suggest that this might be favored by an innate immune reaction against bacterial particles, such as CpG DNA.     

Histological recurrence of autoimmune liver diseases after living-donor liver transplantation

Background:  The effects of living donor liver transplantation (LDLT) on the recurrence of autoimmune liver diseases have not been well documented. Genetic similarities may be beneficial to avoid severe rejection but may facilitate the recurrence of autoimmune diseases. Because familial occurrence of autoimmune liver diseases has been documented, there is a possibility that candidates for living-related donors may have the same disease as that of the recipients.
Method:  Between November 1994 and June 2004, 50 patients with primary biliary cirrhosis (PBC) (16-non-blood-relative donors and 34 blood-relative donors), and 28 patients with primary sclerosing cholangitis (PSC) underwent LDLT in Kyoto University Hospital.
Results:  Among 35 patients with PBC who survived more than 1 year, 10 patients (29%) showed recurrent PBC, and nine of 10 patients with recurrent PBC (90%) were associated with blood-relative donors (mean follow-up period, 30 months; range, 2–68). Two recipients had donors with some clinical or histological characteristics of PBC, and their grafts developedrecurrent PBC. Cirrhosis or graft failure was not observed in any patients with recurrent PBC. For PSC patients who survived more than 1 year after LDLT, 13 of 22 (59%) showed PSC-compatible histology and radiological findings (mean follow-up period, 31 months; range, 22–71), and five died or underwent retransplantation. Human leukocyte antigen-DR15 was positively associated with susceptibility to PSC with ulcerative colitis. One donor was revealed to have retroperitoneal fibrosis without evidence of sclerosing cholangitis.
Conclusions:  Blood-relative donors may be associated with susceptibility to recurrent autoimmune diseases. Recurrence of PSC, but not PBC, adversely affected the outcome of LDLT. Caution should be taken as blood-relative donors can be at risk of autoimmune liver diseases.     

CD3单抗和淋巴细胞功能相关抗原-1对狼疮肾炎外周血单个核细胞的共刺激作用

目的：探讨CD3单抗（mAb)和淋巴细胞功能相关抗原－1单抗（LFA－1mAb)对狼疮肾炎（LN）患者外周血单个核细胞（PBMC）的共刺激作用。方法：2例LN患者被分为活动期（n=14)和非活动期（n=15)，以12例健康献血员为对照，观察CD3mAb或（和）LFA－1mAb共刺激及阻断1－磷酯酰肌醇3－激酶（PI3－K）对体外培养96h后PBMC增生和IL－2产生的影响。PBMC提取采用Ficoll密度梯度离心法，细胞增生实验采用^3H-TdR掺入法，IL－2测定采用ELISA法。结果：PBMC培养96h后，自然生长的LN非活动期和活动期PBMC ^3H-TdR掺入量和IL－2合成与正常对照无明显差异（P值均＞0或0．05）；与自然生长的PBMC相比，CD3mAb单独处理增加了LN非活动期（P值均＜0．05）和活动期（P值均＜0．05）PBMC^3H-TdR掺入量和IL－2合成。而单独CD3mAb对正常对照PBMC^3H-TdR掺入量和IL－2合成没有影响（P值均＞0．05）。与CD3mAb单独处理组相比，CD3mAb和LFA－1mAb共刺激均增加了LN活动期（P值均＜0．05）和非活动期（P值均＜0．05）及正常对照（P值均＜0．05）PBMC ^3H-TdR掺入量和IL－2合成；与对照组相比，CD3mAb和LFA－1mAb共刺激后活动期（P值均＜0．01）和非活动期（P值均＜0．01）PBMC^3H-TdR掺入量和IL－2合成均增加，但活动期效应明显强于非活动期（P＜0．01）。PI3－K特异抑制剂Wortmannin(WT)的加入明显抑制了CD3mAb和LFA－1mAb共刺激诱导的PBMC增生和IL－2的分泌效应（P＜0．01，P＜0．01）。结论：CD3和FLA－1对狼疮肾炎PBMC具有共刺激作用，这种共刺激作用可能参与了狼疮肾炎T、B细胞的异常活化，阻断共刺激传递信号分子PI3－K则能抑制CD3和LFA－1介导的共刺激作用。     

Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART

Objectives We have previously described immune restoration diseases (IRD) associated with asymptomatic opportunistic infections presenting in immunodeficient HIV patients responding to highly active antiretroviral therapy (HAART). Here we address the question of whether patients with a history of IRD exhibit persistent immune activation, shown by elevated levels of interleukin‐(IL)‐6 and soluble IL‐6 receptor (sIL‐6R).
Methods Peripheral blood mononuclear cells (PBMCs) and plasma were collected from HIV patients with nadir CD4 T cell counts of < 80/µL and who had achieved immune reconstitution after HAART with ( n =14) or without ( n =15) experiencing IRD, severely immunodeficient (SID) patients with < 80 CD4 T cells/µL ( n =8) and HIV seronegative controls ( n =15). PBMC production and plasma levels of IL‐6, sIL‐6R and interferon (IFN)‐γ (PBMC only) were measured by enzyme linked immunosorbent assay (ELISA). Intracellular flow cytometry was used to determine the predominant cellular source of IL‐6 in HIV patients and controls.
Results Unstimulated PBMC from IRD patients produced significantly higher amounts of IL‐6 and sIL‐6R than non‐IRD patients and HIV seronegative controls. The sIL‐6R concentration was also significantly higher in supernatants from mitogen‐stimulated PBMC from IRD patients compared to non‐IRD patients. The production of IFN‐γ did not differ between IRD and non‐IRD patients. IRD patients had significantly higher plasma levels of IL‐6 compared to non‐IRD patients, SID patients and controls. Monocytes were the predominant source of IL‐6 in both HIV patients and controls.
Conclusions Patients with a history of IRD after HAART have elevated levels of IL‐6 and sIL‐6R.     

Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma

Although immunosuppression has long been recognized in Hodgkin lymphoma (HL), the underlying basis for the lack of an effective immune response against the tumor remains unclear. The aim was to test our hypothesis that regulatory T cells dominate involved lymph nodes. The approach was to assay CD4+ T-cell function in HL-infiltrating lymphocytes (HLILs) and paired peripheral blood mononuclear cells (PBMCs) of 24 patients. Strikingly, unlike PBMCs, HLILs were anergic to stimulation with mitogen, primary, or recall antigens, mounting no proliferative responses and only rare T-helper 1 (Th1) or Th2 cytokine responses. Mixing paired HLILs and PBMCs showed the anergic effect was dominant and suppressed PBMC responses. Furthermore, flow cytometry demonstrated that HLILs contained large populations of both interleukin-10 (IL-10)-secreting T-regulatory 1 (Tr1) and CD4+CD25+ regulatory T cells. We found evidence for 3 mechanisms of action implicated in the suppressive functions of regulatory T cells: the inhibition of PBMCs by HLILs was ameliorated by neutralizing IL-10, by preventing cell-to-cell contact, and by blocking anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4). Thus, HLILs are highly enriched for regulatory T cells, which induce a profoundly immunosuppressive environment and so provide an explanation for the ineffective immune clearance of Hodgkin-Reed Sternberg cells.     

CD4(+) and CD8(+) anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity

Interleukin-10 (IL-10)-treated dendritic cells (DCs) induce an alloantigen- or peptide-specific anergy in various CD4(+) and CD8(+) T-cell populations. In the present study, we analyzed whether these anergic T cells are able to regulate antigen-specific immunity. Coculture experiments revealed that alloantigen-specific anergic CD4(+) and CD8(+) T cells suppressed proliferation of syngeneic T cells in a dose-dependent manner. The same effect was observed when the hemagglutinin-specific CD4(+) T-cell clone HA1.7 or tyrosinase-specific CD8(+) T cells were cocultured with anergic T cells of the same specificity. Anergic T cells did not induce an antigen-independent bystander inhibition. Suppression was dependent on cell-to-cell contact between anergic and responder T cells, required activation by antigen-loaded DCs, and was not mediated by supernatants of anergic T cells. Furthermore, anergic T cells displayed an increased extracellular and intracellular expression of cytotoxic T-lymphocyte antigen (CTLA)-4 molecules, and blocking of the CTLA-4 pathway restored the T-cell proliferation up to 70%, indicating an important role of the CTLA-4 molecule in the suppressor activity of anergic T cells. Taken together, our experiments demonstrate that anergic T cells induced by IL-10-treated DCs are able to suppress activation and function of T cells in an antigen-specific manner. Induction of anergic T cells might be exploited therapeutically for suppression of cellular immune responses in allergic or autoimmune diseases with identified (auto) antigens.     

Antilactoferrin Antibodies in Autoimmune Liver Diseases

Objective: Lactoferrin, an immunoregulatory protein in mucosal secretions, is one of the target antigens to perinuclear antineutrophil cytoplasmic antibodies (P-ANCAs). Circulating lactoferrin is cleared in the liver, but little is known about the implication of lactoferrin in hepatic inflammation. To evaluate the implication of immunological response to lactoferrin, we examined antilactoferrin antibodies in autoimmune liver diseases.
Methods: Fourteen patients with primary biliary cirrhosis (PBC), 14 with autoimmune hepatitis (AIH), five with autoimmune cholangitis (AIC), six with chronic hepatitis C, and five with chronic hepatitis B were studied. We evaluated autoantibodies to lactoferrin in the sera of the patients by the Western Immunoblotting method.
Results: Sera of five of the 14 patients (35.7%) with PBC, four of the 14 patients (28.6%) with AIH, and five of the five patients (100%) with AIC contained autoantibodies to human lactoferrin, but none with hepatitis B or C had them. The higher prevalence of serum antibodies to human lactoferrin was shown to be higher in patients with AIC than with hepatitis B (   p < 0.01  ), hepatitis C (   p < 0.01  ), PBC (   p < 0.05  ), and AIH (   p < 0.05  ).
Conclusion: Lactoferrin located in bile ducts and liver cells is one of the candidates of target antigens in autoimmune liver diseases, especially in AIC.     

Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions.

B-cell tolerance to soluble protein self antigens such as hen egg lysozyme (HEL) is mediated by clonal anergy. Anergic B cells fail to mount antibody responses even in the presence of carrier-primed T cells, suggesting an inability to activate or respond to T helper cells. To investigate the nature of this defect, B cells from tolerant HEL/anti-HEL double-transgenic mice were incubated with a membrane preparation from activated T-cell clones expressing the CD40 ligand. These membranes, together with interleukin 4 and 5 deliver the downstream antigen-independent CD40-dependent B-cell-activating signals required for productive T-B collaboration. Anergic B cells responded to this stimulus by proliferating and secreting antibody at levels comparable to or better than control B cells. Furthermore, anergic B cells presented HEL acquired in vivo and could present the unrelated antigen, conalbumin, targeted for processing via surface IgD. In contrast, the low immunoglobulin receptor levels on anergic B cells were associated with reduced de novo presentation of HEL and a failure to upregulate costimulatory ligands for CD28. These defects in immunoglobulin-receptor-mediated functions could be overcome in vivo, suggesting a number of mechanisms for induction of autoantibody responses.     

Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo

T-cell anergy is a tolerance mechanism defined as a hyporesponsive status of antigen-specific T cells upon prior antigen encounter and is believed to play a critical role in the evasion of tumor immunity and the amelioration of allogeneic transplant rejection. Molecular mechanisms in controlling T-cell anergy are less known. We show here that administration of an agonistic monoclonal antibody (mAb) to CD137, a member of the tumor necrosis factor receptor superfamily, prevents the induction of CD8+ cytolytic T-lymphocyte (CTL) anergy by soluble antigens. More importantly, CD137 mAb restores the functions of established anergic CTLs upon reencountering their cognate antigen. As a result, infusion of CD137 mAb inhibits progressive tumor growth that is caused by soluble tumor antigen-induced tolerance in a P815R model. CD137 mAb also restores proliferation and effector functions of anergic alloreactive 2C T cells in a bone marrow transplantation model. Our results indicate that ligation of CD137 receptor delivers a regulatory signal for T-cell anergy and implicate manipulation of the CD137 pathway as a new approach to break T-cell tolerance.     

Anergy in patients with gastric cancer

A prospective study of delayed hypersensitivity was carried out in gastric cancer patients. One hundred and fifty-six subjects were studied. Fifty-nine were controls and ninety-nine patients with gastric neoplasm. A multitest technique was used to evaluate the delayed hypersensitivity response, classifying the subjects into one of three groups: immunocompetent, relatively anergic, and anergic. In the control group, 76% per cent of the subjects were immunocompetent; of the patients, only 43% showed an adequate cell-mediated immune response (p less than 0.001). Fourteen control subjects (24%) and 54 patients (56%) presented with either anergy or relative anergy (p less than 0.001). Of the ninety-four patients that underwent surgery, five (11.9%) of the immunocompetent group developed major postoperative septic complications, as did seven (22%) of the relative anergic and seven (35%) of the anergic patients (immunocompetent vs. anergic, p less than 0.05). Our study indicates a relationship between anergy and postoperative septic complications.