The effect of polymyxin B hemoperfusion on modulation of human leukocyte antigen DR in severe sepsis patients.

BACKGROUND: Recent randomized trials have not found that polymyxin B hemoperfusion (PMX-HP) improves outcomes for patients with sepsis. However, it remains unclear whether the therapy could provide benefit for highly selected patients. Monocyte human leukocyte antigen (mHLA-DR) expression, a critical step in the immune response, is decreased during sepsis and leads to worsening sepsis outcomes. One recent study found that PMX-HP increased mHLA-DR expression while another found that the treatment removed HLA-DR-positive cells. METHODS: We conducted a randomized controlled trial in patients with blood endotoxin activity assay (EAA) level ≥ 0.6. Patients in the PMX-HP group received a 2-h PMX-HP treatment plus standard treatment for 2 consecutive days. Patients in the non-PMX-HP group received only standard treatment. The primary outcome compared the groups on median change in mHLA-DR expression between day 3 and baseline. Secondary outcomes compared the groups on the mean or median change in CD11b expression, neutrophil chemotaxis, presepsin, cardiovascular Sequential Organ Failure Assessment (CVS SOFA) score, vasopressor dose, and EAA level between day 3 and baseline. We further compared the groups on mortality, ICU-free days, ventilator-free days, dialysis dependence status, renal recovery, serum creatinine, vasopressor-free days, and major adverse kidney events (MAKE 28), measured on day 28. RESULTS: Fifty-nine patients were randomized to PMX-HP (n = 29) and non-PMX-HP (n = 30) groups. At baseline, mHLA-DR expression, CD11b, neutrophil chemotaxis, and clinical parameters were comparable between groups. The median change in mHLA-DR expression between day 3 and baseline was higher in PMX-HP patients than in patients receiving standard therapy alone (P = 0.027). The mean change in CD11b between day 3 and baseline was significantly lower in the PMX-HP group than in the non-PMX-HP group (P = 0.002). There were no significant changes from baseline in neutrophil chemotaxis, presepsin, CVS SOFA scores, vasopressor doses, or EAA level between groups. On day 28 after enrollment, mortality, ICU-free days, ventilator-free days, dialysis dependence status, renal recovery, serum creatinine, vasopressor-free days, and MAKE 28 were comparable between groups. CONCLUSION: PMX-HP improved mHLA-DR expression in severe sepsis patients. Future studies should examine the potential benefit of PMX-HP in patients with low mHLA-DR expression. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02413541 . Registered on 3 March 2015.

Effects of dexmedetomidine on CD42a+/CD14+, HLADR+/CD14+ and inflammatory cytokine levels in patients undergoing multilevel spinal fusion.

OBJECTIVE: To assess the effects of dexmedetomidine (Dex) on CD42a+/CD14+，HLADR+/CD14+ and inflammatory cytokine levels in patients undergoing multilevel spinal fusion. Patients and methods Forty ASA I-II patients undergoing multilevel spinal fusion were randomly divided into Dex and control groups (n=20). A continuous intravenous infusion of Dex (0.5µg/kg/h) or normal saline was started 10min prior to induction and was stopped 15min before operation completion. Serum levels of CD42a+/CD14+, HLADR+/CD14+, WBC, PLT, CRP, IL-6, IL-10, and TNF-α were measured before induction (T1), 30min (T2) after operation initiation, and 60min (T3), 1d (T4), 3d (T5), and 5d (T6) post-operation. VAS values were obtained at T3, T4, T5 and T6, as well as hospital days. RESULTS: Treatment with Dex significantly decreased CD42a+/CD14+ at T2, T3, and T4, and markedly increased HLADR+/CD14+ at T4 and T5 when compared with controls. CRP and WBC were markedly decreased at T2, T3, T4 and T5 (P<0.01 or P<0.05). Serum IL-6 and TNF-α level in Dex group was significantly increased at T3 and T4 (P<0.05), and IL-6 and TNF-α level in control group was significantly increased at T2, T3, T4 and T5 (P<0.05) when compared with their respective preoperative levels (T1). IL-6 and TNF-α levels at T2, T3, T4 and T5 in Dex group were significantly lower than those in control group (P<0.05). There were no significant differences in operation time, hospital days or VAS values between the two groups (P>0.05). CONCLUSION: Dex can inhibit the inflammatory response and reduce immunosuppression in patients undergoing multilevel spinal fusion.

FGF2 induces RANKL gene expression as well as IL1ß regulated MHC class II in human bone marrow-derived mesenchymal progenitor stromal cells.

OBJECTIVE: Human bone marrow mesenchymal stromal cells (hBM-MSC) are being applied in tissue regeneration and treatment of autoimmune diseases (AD). Their cellular and immunophenotype depend on isolation and culture conditions which may influence their therapeutic application and reflect their in vivo biological functions. We have further characterised the phenotype induced by fibroblast growth factor 2 (FGF2) on healthy donor hBM-MSC focusing on the osteoimmunological markers osteoprotegerin (OPG), receptor activator of nuclear factor kB (RANK), RANK ligand (RANKL) and HLA-DR and their regulation of expression by the inflammatory cytokines IL1ß and IFNγ. METHODS: RANK, RANKL, OPG and HLA-DR expression in hBM-MSC expanded under specific culture conditions, were measured by RT-PCR and flow cytometry. MAPKs induction by FGF2, IL1ß and IFNγ in hBM-MSC was analysed by immunoblotting and RT-PCR. RESULTS: In hBM-MSC, OPG expression is constitutive and FGF2 independent. RANKL expression depends on FGF2 and ERK1/2 activation. IL1ß and IFNγ activate ERK1/2 but fail to induce RANKL. Only IL1ß induces P38MAPK. The previously described HLA-DR induced by FGF2 through ERK1/2 on hBM-MSC, is suppressed by IL1ß through inhibition of CIITA transcription. HLA-DR induced by IFNγ is not affected by IL1ß in hBM-MSC, but is suppressed in articular chondrocytes and lung fibroblasts. CONCLUSIONS: RANKL expression and IL1ß regulated MHC-class II, both induced via activation of the ERK1/2 signalling pathway, are specific for progenitor hBM-MSC expanded in the presence of FGF2. HLA-DR regulated by IL1ß and ERK1/2 is observed on hBM-MSC during early expansion without FGF2 suggesting previous in vivo acquisition. Stromal progenitor cells with this phenotype could have an osteoimmunological role during bone regeneration.

Protective effects of ulinastatin on pulmonary damage in rats following scald injury.

Organ protection is desirable in severe burn/scald injuries, and damage mechanisms and thus effective therapies following scald injury have not been fully elucidated. Our aim was to examine the beneficial effects of ulinastatin on pulmonary damage associated with scald injury. Lewis rats were subjected to 30% total body surface area (TBSA) scald injury and were randomly divided into a burn control (S group) and an ulinastatin-treated group (U group). Lung malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined, and the lungs were examined histologically with immunohistochemistry (IHC) as well for the major histocompatibility complex (MHC) class I chain-related antigen A (MICA) and Bcl-2 at 24, 48 and 72 h after the injury. The expression of spleen human leucocyte antigen-DR (HLA-DR) was detected by immunohistochemistry analysis. Selectins and adhesion molecules in lungs and serum were also detected. The lung injury degree was represented as wet/dry (W/D) values and alveolar thickness. Ulinastatin decreased MDA levels and ameliorated the down-regulation of SOD activity. MICA was up-regulated after the scald, and this up-regulation was greatly diminished by ulinastatin. Bcl-2 was up-regulated after the scald, especially in the U group. The spleen HLA-DR expression demonstrated the immunoregulatory effects of ulinastatin, which effectively protected the pulmonary tissues from scald-induced injury. Our results demonstrated that pulmonary damage was associated with autoimmunity and oxidant attack after severe scald. Ulinastatin exhibits significant protective effects on these effects.

Response of monocyte-derived dendritic cells to rapidly solidified nickel-titanium ribbons with shape memory properties.

Ni-Ti Shape Memory Alloys (SMAs) have attracted considerable attention as biomaterials for medical devices. However, the biocompatibility of Ni-Ti SMAs is often unsatisfactory due to their poor surface structure. Here we prepared Rapidly Solidified (RS) Ni-Ti SMA ribbons by melt-spinning and their surface was characterised by Auger-electron spectroscopy, X-ray photoelectron spectrometry and scanning electron microscopy. The biocompatibility of the produced ribbons and their immunomodulatory properties were studied on human monocyte-derived dendritic cells (MoDCs). We showed that melt-spinning of Ni-Ti SMAs can form a thin homogenous oxide layer, which improves their corrosion resistance and subsequent toxicity to MoDCs. Ni-Ti RS ribbons stimulated the maturation of MoDCs, as detected by changes in the cells' morphology and increased expression of HLA-DR, CD86, CD40 and CD83 molecules. However, Ni-Ti RS ribbons enhanced the tolerogenic properties of immature MoDCs, which produced higher levels of IL-10 and IL-27, driving the differentiation of IL-10- and TGF-ß-producing CD4+T cells. On the other hand, in the presence of lipopolysaccharide, an important pro-inflammatory biomolecule, Ni-Ti RS ribbons enhanced the allostimulatory and Th1 polarising capacity of MoDCs, whereas the production of Th2 and Th17 cytokines was down-regulated. In conclusion, Ni-Ti RS ribbons possess substantial immunomodulatory properties on MoDCs. These findings might be clinically relevant, because implanted Ni-Ti SMA devices can induce both desired and adverse effects on the immune system, depending on the microenvironmental stimuli.

Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy.

Cytotoxic T-lymphocyte-associated antigen (CTLA-4), also known as CD152, is a co-inhibitory molecule that functions to regulate T-cell activation. Antibodies that block the interaction of CTLA-4 with its ligands B7.1 and B7.2 can enhance immune responses, including antitumor immunity. Two CTLA-4-blocking antibodies are presently under clinical investigation: ipilimumab and tremelimumab. CTLA-4 blockade has shown promise in treatment of patients with metastatic melanoma, with a recently completed randomized, double-blind phase III trial demonstrating a benefit in overall survival (OS) in the treated population. However, this approach appears to benefit only a subset of patients. Understanding the mechanism(s) of action of CTLA-4 blockade and identifying prognostic immunologic correlates of clinical endpoints to monitor are presently areas of intense investigation. Several immunologic endpoints have been proposed to correlate with clinical activity. This review will focus on the endpoints of immune monitoring described in studies to date and discuss future areas of additional work needed.

Association of HLA-DR14 with the treatment response in Japanese patients with autoimmune hepatitis.

BACKGROUND: Influence of human lymphocyte antigen (HLA) on the therapeutic response in autoimmune hepatitis (AIH) is not known. AIMS: To evaluate if HLA-DR types influence biological and histological responses to corticosteroids in patients with AIH. METHODS: During 28 years from 1979 through 2007, 48 patients with definite diagnosis of AIH received long-term corticosteroid therapy (median 9 years [range: 5-28 years]) in a single Japanese center. They were followed for transaminase levels and received liver biopsy before and after the treatment. RESULTS: DR4 was detected in 32 and DR14 in 11 patients; seven possessed both DR4 and DR14. DR4 was more frequent in AIH patients than in the general population (67% vs. 22%), while DR14 was comparably frequent between them (23% vs. 17%). Overall, biochemical response was achieved in 43 (90%) of the 48 patients. The sustained biochemical response to a maintenance prednisolone dose < 10 mg was gained more frequently in the patients with than without DR14 (10/11 [91%] vs. 10/37 [27%], P < 0.001). Marked histological improvement with a decrease in histology activity index (HAI) score by > 2 points was achieved in 31 of the 32 (97%) biochemical responders. Histological aggravation with an increase in HAI score occurred in 4 of the 16 (25%) patients without biochemical response (non-responders and relapsers combined), but in none of the 32 responders. CONCLUSION: Long-term immunosuppressive treatment can improve the outcome of Japanese patients with AIH, and DR14 is associated with excellent biochemical response.

The glutathione-S-transferase Mu 1 null genotype modulates ozone-induced airway inflammation in human subjects.

BACKGROUND: The glutathione-S-transferase Mu 1 (GSTM1) null genotype has been reported to be a risk factor for acute respiratory disease associated with increases in ambient air ozone levels. Ozone is known to cause an immediate decrease in lung function and increased airway inflammation. However, it is not known whether GSTM1 modulates these ozone responses in vivo in human subjects. OBJECTIVE: The purpose of this study was to determine whether the GSTM1 null genotype modulates ozone responses in human subjects. METHODS: Thirty-five healthy volunteers were genotyped for the GSTM1 null mutation and underwent a standard ozone exposure protocol to determine whether lung function and inflammatory responses to ozone were different between the 19 GSTM1 wild type and 16 GSTM1 null volunteers. RESULTS: GSTM1 did not modulate lung function responses to acute ozone. Granulocyte influx 4 hours after challenge was similar between GSTM1 normal and null volunteers. However, GSTM1 null volunteers had significantly increased airway neutrophils 24 hours after challenge, as well as increased expression of HLA-DR on airway macrophages and dendritic cells. CONCLUSION: The GSTM1 null genotype is associated with increased airways inflammation 24 hours after ozone exposure, which is consistent with the lag time observed between increased ambient air ozone exposure and exacerbations of lung disease.

Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial.

RATIONALE: Sustained sepsis-associated immunosuppression is associated with uncontrolled infection, multiple organ dysfunction, and death. OBJECTIVES: In the first controlled biomarker-guided immunostimulatory trial in sepsis, we tested whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reverses monocyte deactivation, a hallmark of sepsis-associated immunosuppression (primary endpoint), and improves the immunological and clinical course of patients with sepsis. METHODS: In a prospective, randomized, double-blind, placebo-controlled, multicenter trial, 38 patients (19/group) with severe sepsis or septic shock and sepsis-associated immunosuppression (monocytic HLA-DR [mHLA-DR] <8,000 monoclonal antibodies (mAb) per cell for 2 d) were treated with GM-CSF (4 microg/kg/d) or placebo for 8 days. The patients' clinical and immunological course was followed up for 28 days. MEASUREMENTS AND MAIN RESULTS: Both groups showed comparable baseline mHLA-DR levels (5,609 +/- 3,628 vs. 5,659 +/- 3,332 mAb per cell), which significantly increased within 24 hours in the GM-CSF group. After GM-CSF treatment, mHLA-DR was normalized in 19/19 treated patients, whereas this occurred in 3/19 control subjects only (P < 0.001). GM-CSF also restored ex-vivo Toll-like receptor 2/4-induced proinflammatory monocytic cytokine production. In patients receiving GM-CSF, a shorter time of mechanical ventilation (148 +/- 103 vs. 207 +/- 58 h, P = 0.04), an improved Acute Physiology and Chronic Health Evaluation-II score (P = 0.02), and a shorter length of both intrahospital and intensive care unit stay was observed (59 +/- 33 vs. 69 +/- 46 and 41 +/- 26 vs. 52 +/- 39 d, respectively, both not significant). Side effects related to the intervention were not noted. CONCLUSIONS: Biomarker-guided GM-CSF therapy in sepsis is safe and effective for restoring monocytic immunocompetence. Use of GM-CSF may shorten the time of mechanical ventilation and hospital/intensive care unit stay. A multicenter trial powered for the improvement of clinical parameters and mortality as primary endpoints seems indicated. Clinical trial registered with www.clinicaltrials.gov (NCT00252915).

[Efficacy of local use of recombinant interferon alpha-2 preparations in combined treatment of recurrent respiratory papillomatosis].

Clinical-immunological examination of 41 patients with recurrent respiratory papillomatosis (RRP) included determination of phenotype CD3, CD4, CD8, CD16, CD25, CD56, HLA-DR in peripheral blood by flow cytofluorimetry, the levels of IFN-gamma, TNF-alpha, GM-CSF, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13 in the laryngeal secretion by multiplex immunoassay. Interferon inhalation therapy was conducted to prevent recurrence in 23 patients after surgical treatment and in 18 patients as monotherapy. The efficacy of the monotherapy was 45.5%. Treatment with IFN-alpha raised the levels of cytokines modulating an immune response by Th1-type (IFN-gamma, IL-12, IL-2) and GM-CSF, and reduced the levels of IL-4, IL-10 and IL-13. Local treatment with recombinant IFN-alpha is effective in aggressive RRP. As prognostic markers of the treatment efficacy may serve baseline high levels of TNF-alpha and IL-4/IFN-gamma index in laryngeal secretion. Treatment efficacy can be assessed by raise of IFN-gamma, IL-2 and IL-12 in combination with reduction of IL-4/IFN-gamma index.

Effects of IL-17 on human gingival fibroblasts.

Interleukin (IL)-17 is present in inflammatory periodontal lesions, thus suggesting a role in mediating inflammation. We tested the hypothesis that IL-17, especially when combined with interferon (IFN)-gamma, may modulate the responses of human gingival fibroblasts (HGFs). IL-17 induced IL-8 and minimal intercellular adhesion molecule (ICAM)-1 expression. It had no effect on expression of HLA-DR, CD40, or the immune-suppressive enzyme indoleamine 2,3-dioxygenase (IDO). The effects of IL-17 on HGFs were compared with those of IFN-gamma. Unlike IL-17, IFN-gamma augmented the expression of HLA-DR, ICAM-1, and IDO, but not IL-8. Thus, IL-17 and IFN-gamma induce different HGF responses when administered separately. Interestingly, when IL-17 and IFN-gamma were combined, marked enhancement of ICAM-1, IL-8, and IDO expression by HGFs was observed. These findings suggest that IL-17, especially when combined with IFN-gamma, could play an important role in immune modulation through stimulation of HGFs in periodontal disease.

Topical treatment of mild to moderate plaque psoriasis with 0.3% tacrolimus gel and 0.5% tacrolimus cream: the effect on SUM score, epidermal proliferation, keratinization, T-cell subsets and HLA-DR expression.

BACKGROUND: Tacrolimus gel 0.3% and tacrolimus cream 0.5% were studied and compared with calcipotriol ointment 0.005%, as topical treatment for mild to moderate plaque psoriasis. Tacrolimus is able to inhibit several cellular processes thought to be important in the pathogenesis of psoriasis, e.g. the transcription of proinflammatory cytokines, keratinocyte hyperproliferation and the expression of HLA-DR in lesional psoriatic skin. METHOD: In the present study we investigated the effects of preparations of tacrolimus and calcipotriol ointment on SUM score, hyperproliferation (Ki67-positive keratinocytes), keratinization (percentage keratin 10 (K10)-positive epidermal surface), T-cell subsets (CD4, CD8, CD45RO, CD45RA, CD2, CD25), cells expressing natural killer receptors and HLA-DR expression. The following three topical treatments were studied in chronic plaque psoriasis over a 12-week treatment period: calcipotriol ointment 0.005% twice daily, tacrolimus gel 0.3% twice daily and tacrolimus cream 0.5% twice daily. RESULTS: The mean reductions in SUM score between day 0 and week 12 for calcipotriol ointment, tacrolimus gel and cream were significant. Calcipotriol ointment, and tacrolimus gel and cream had a comparable effect on epidermal proliferation (Ki67-positive cells), but calcipotriol is significantly more effective in normalizing differentiation (K10-positive epidermal surface). Calcipotriol and tacrolimus gel both reduced several lesional T-cell subsets significantly, whereas the effect induced by tacrolimus cream was modest. CONCLUSIONS: Calcipotriol and tacrolimus gel are comparable in reducing the SUM score, the number of Ki67-positive cells and T-cell subsets and HLA-DR expression, although calcipotriol induces a more substantial improvement of keratinization.

Differential suppression of dendritic cell cytokine production by anti-inflammatory drugs.

BACKGROUND: Various anti-inflammatory drugs are available for the treatment of skin disorders. In these diseases, untoward immune responses to endogenous and/or environmental antigens are initiated by maturation and polarization of dendritic cells (DC). OBJECTIVE: To explore the suppressive effects of anti-inflammatory drugs on DC maturation and, in particular, polarization. METHODS: Exposure of DC to nickel in vitro results in DC maturation and secretion of both type 1 and type 2 cytokines, thereby providing a model to study the effects of anti-inflammatory drugs on DC responses. The inhibitory effects of anti-inflammatory drugs (ciclosporin, dexamethasone, diclofenac, dimethylfumarate, hydrocortisone, lactoferrin, 1-alpha,25-dihydroxyvitamin D3) on DC maturation (CD83, CD86, HLA-DR, CXCL8) and polarization (type 1: IL-12p70, TNF-alpha; type 2: IL-10, CCL17) were studied. RESULTS: All anti-inflammatory drugs, except for lactoferrin, had inhibitory effects on DC maturation. Hydrocortisone and dexamethasone exclusively suppressed the release of type 1 cytokines. A less pronounced, but similar profile was observed for dimethylfumarate and 1-alpha,25-dihydroxyvitamin D3. Ciclosporin suppressed both type 1 and 2 cytokines. In contrast, diclofenac suppressed only type 2 DC cytokine secretion. CONCLUSION: The present results give more insight into the pharmacological effects of immunosuppressive drugs on the immune system, and can thereby contribute to a more rational selection of anti-inflammatory drugs for the treatment of inflammatory skin disorders.

Insulin in the critically ill with focus on cytokines, reactive oxygen species, HLA-DR expression.

Insulin is essential for glucose homeostasis. Insulin/glucose-insulin-potassium (GIK) regimen suppresses the production of tumor necrosis factor-alpha (TNF-alpha), interleukins-6 (IL-6), macrophage migration inhibitory factor (MIF) and other pro-inflammatory cytokines and reactive oxygen species (ROS), enhances the synthesis of endothelial nitric oxide (eNO), and anti-inflammatory cytokines interleukins-4 (IL-4) and interleukin-10 (IL-10). In subjects who are critically ill, monocyte HLA-DR expression was significantly decreased with a concomitant increase in plasma IL-10 and IL-4 concentrations. Large increases in the plasma concentrations of TNF-alpha, IL-6, sustained increase in the expression of leukocyte CD11b/CD18, and ROS generation following surgery and infections were found to be associated with increased mortality. By virtue of its actions on pro- and anti-inflammatory cytokines and ROS, insulin may have the ability to alter HLA-DR expression in the critically ill and thus bring about its beneficial actions in sepsis/septic shock, myocardial recovery following acute myocardial infarction, improve prognosis of those who are critically ill, and suppress inflammation.

Endotoxemia contributes to the immune paralysis in patients with cirrhosis.

BACKGROUND/AIMS: Immune paralysis, defined as decreased HLA-DR expression on monocytes and indicated immune dysfunctions, was found in sepsis, severe acute pancreatitis and acute liver failure. However, the relationship between HLA-DR expression and cirrhosis is unclear. METHODS: We enrolled 64 patients with liver cirrhosis and 23 healthy volunteers. HLA-DR expressions, functions of monocyte, serum cytokines and endotoxin levels were measured. RESULTS: Compared to healthy volunteers, HLA-DR expressions were significantly lower in Child-Pugh class C cirrhotic patients (89.28% vs 69.29%, p<0.001). These low-HLA-DR-expressed monocytes were with decreased ability of tumor necrosis factor (TNF)-alpha secretion, decreased expression of inducible nitric oxide synthetase (iNOS) and decreased allo-stimulatory ability but normal phagocytosis ability. The co-stimulatory molecules like CD40 and CD86 were down-regulated as well but not CD80. Furthermore, HLA-DR expression was linearly correlated with the presence of hepatic encephalopathy (r(2)=0.2642; p=0.008) and serum interleukin-10 (IL-10) (r(2)=0.2167; p=0.019) in patients with Child-Pugh class C. Serum endotoxin level was in linear relationship to serum IL-10 level (r(2)=0.1868; p=0.002) and HLA-DR expression (r(2)=0.0924; p=0.036). In addition, endotoxin, mediated by IL-10, could down-regulate the HLA-DR expression. CONCLUSIONS: Child-Pugh class C cirrhotic patients suffer from down-regulation of HLA-DR expression. Endotoxemia, possibly mediated by IL-10, contributes to this HLA-DR down-regulation.

Second-generation peptidomimetic inhibitors of antigen presentation effectively treat autoimmune diseases in HLA-DR-transgenic mouse models.

Peptidomimetic compounds that bind to major histocompatibility complex class II molecules and are resistant to cathepsins can competitively inhibit the presentation of processed protein antigens. Therefore, compounds that bind to autoimmune disease-associated class II molecules are expected to compete with autoantigens for presentation and thereby interrupt the disease process. The first generation of such competitors developed for rheumatoid arthritis-associated HLA-DR molecules, although resistant to cathepsins, has remained sensitive to plasma proteases, and was thus unlikely to be effective in vivo. We have therefore produced a second generation of compounds that are resistant to cathepsins and stable in plasma while maintaining binding affinity for HLA-DR molecules associated with rheumatoid arthritis and multiple sclerosis. Selected compounds of this series are shown to inhibit antigen presentation in vivo, as well as effectively treat collagen induced arthritis and experimental autoimmune encephalomyelitis in HLA-DR transgenic mouse models.

Association between human leukocyte antigen (HLA) and interferon- induced thyroid diseases in four patients with HCV-related chronic hepatitis.

OBJECTIVES: The interferon-alpha (IFN-alpha) therapy for HCV hepatitis may exacerbate or induce underlying thyroid disorders. Besides viral factors, the human leukocyte antigen (HLA) may be an independent risk factor. METHODS: We evaluated fifteen patients with HCV chronic hepatitis during a period of 40 months. At the enrollment, all the patients were negative for thyroid disorders, excluding one patient with subclinical hypothyroidism. Eleven patients received IFN-alpha therapy. The HLA system was examined in every patient, evaluating antigens (n=40) of locus A, B and Cw and alleles (n=19) of locus DRB1* and DQB1*. The HLA system was also examined in healthy subjects (n=107) as a control group. RESULTS: The HCV genotype distribution in patients was: 1b=20%, 2a=60%, 3a=20%. Four IFN-treated patients presented clinical thyroid disorders, including autoimmune hypothyroidism (n=2), transient thyrotoxicosis (n=1) and subacute thyroiditis (n=1). The HLA susceptibility to thyroid disorders (antigen/allele frequency) in the whole group of patients was not different in respect to controls and normal Italian population. The patients with HCV chronic hepatitis that developed thyroid diseases after IFN- treatment had a double and specific association with the HLA system (Mantel-Haenszel X(c)(2)=4.706, p<0.05). CONCLUSIONS: This case report suggests that HLA system examination is an important and promising diagnostic aspect that may be considered in order to evaluate the appearance of thyroid disorders during the IFN-alpha treatment for HCV-related chronic hepatitis.

Hepatitis C virus genotypes, HLA-DRB alleles and their response to interferon-alpha and ribavirin in patients with chronic hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) is a worldwide common disease. Some predictive factors influencing the response to interferon alpha (IFN-alpha) therapy have been identified, but the conclusions differ in various counties and areas. The aim of this study was to study the associations between HCV genotypes, HLA-DRB alleles and their response to IFN-alpha and ribavirin in Chinese patients with chronic hepatitis C in Northeast China. METHODS: HCV genotypes of 113 patients with HCV were investigated. Gene chips were used to analyze the frequency of HLA-DRB in 25 of these patients and their response to IFN-alpha and ribavirin. The associations of HCV genotypes, HLA-DRB alleles and their response to IFN-alpha and ribavirin were also studied. RESULTS: The response rates differed in several types of HCV, with HCV 2b being the highest (57.78%), HCV 1a and 2a lower (46.15% and 47.62%) and HCV 1b the lowest (11.76%). The response rates to IFN-alpha and ribavirin in patients with DRB1*07 were higher than those with DRB1*04. Sex, HCV type and HLA-DRB were all related to the response. Most female patients with HCV 2b and HLA-DRB1*07 presented complete response, whereas male patients with HCV 1b and HLA-DRB1*04 usually demonstrated no response. DRB1*07 allele and HCV 2b were the factors closely related to the response. CONCLUSIONS: The response rate of HCV 1b may be the lowest even IFN-alpha and ribavirin are combined in treatment. Not only virus but also the host plays an important role in anti-virus therapy. Thus, it is necessary to adjust the host's immune status to accelerate the clearance of HCV.