Phase 2 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease.

Steroid-refractory chronic graft-versus-host disease (cGVHD) after allogeneic transplant remains a significant cause of morbidity and mortality. Abatacept is a selective costimulation modulator, used for the treatment of rheumatologic diseases, and was recently the first drug to be approved by the US Food and Drug Administration for the prophylaxis of acute graft-versus-host disease. We conducted a phase 2 study to evaluate the efficacy of abatacept in steroid-refractory cGVHD. The overall response rate was 58%, seen in 21 out of 36 patients, with all responders achieving a partial response. Abatacept was well tolerated with few serious infectious complications. Immune correlative studies showed a decrease in interleukin -1α (IL-1α), IL-21, and tumor necrosis factor α as well as decreased programmed cell death protein 1 expression by CD4+ T cells in all patients after treatment with abatacept, demonstrating the effect of this drug on the immune microenvironment. The results demonstrate that abatacept is a promising therapeutic strategy for the treatment of cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01954979.

Anti-cyclic citrullinated peptide antibodies and paraoxonase-1 polymorphism in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease, with a worldwide prevalence of 0.5% to 1%. Anti-cyclic citrullinated peptide antibody (anti-CCP-2 Ab) is a marker of choice for diagnosing early and late RA. Anti-oxidant enzymes activity decreases in RA patients. Till now, the relationship between the rheumatoid factor (RF) and anti-CCP-2 Ab, anti-oxidant activity and polymorphism of paraoxenase-1 (PON-1) 192 Q/R in patients with RA has not been investigated. In this study, we aimed to determine the serum level of RF and anti-CCP-2 Ab, PON-1 activity and 192 Q/R polymorphism and arylesterase (ARE) activity in patients with RA. Also, we studied RA markers in different genotypes of PON-1 of RA patients. METHODS: A total of 120 RA patients and 90 healthy persons were subjected to full clinical examinations and routine laboratory tests. PON-1 and ARE activities were determined using an enzymatic spectrophotometric method. PON-1 192 gene polymorphism was determined using polymerase chain reaction based restriction fragment analysis. RF was measured by immunoturbidimetry method and anti-CCP-2 Ab was assayed by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using SPSS for windows 20.0. RESULTS: The sensitivity and specificity of anti-CCP-2 Ab for the diagnosis of RA were 76.2% and 100% respectively. PON-1 and ARE activities were statistically lower (P <0.001) in the RA group compared to the control group. A negative correlation between RF and anti-CCP-2 Ab levels and PON-1 and ARE activities was found. No significant difference in the genotype distribution between RA patients and healthy persons was detected. RF and anti-CCP-2 Ab levels were higher in RA patients carried RR genotype than in those carried QQ genotype. CONCLUSION: High RF and anti-CCP-2 antibody serum levels were found to be associated with decreased PON-1 and ARE activities with no correlation between PON-1 polymorphism and serum levels of RF and anti-CCP-2 Ab in patients with RA. These results may indicate an implication between antioxidant enzymes activity and serum levels of RF and anti-CCP-2 Ab.

Role of Chlamydia pneumoniae, helicobacter pylori and cytomegalovirus in coronary artery disease.

Coronary artery disease (CAD) is the leading cause of death in many countries. The underlying mechanism of the chronic inflammatory process in atherosclerosis is still unknown. As a possible trigger, different viruses and bacteria may be associated with atherosclerotic diseases. The aim of this work was to investigate the association of chronic infection with C pneumoniae, H pylori and cytomegalovirus (CMV) infections and CAD. Fifty patients [20 with acute coronary artery disease (ACAD) and 30 with chronic coronary artery disease (CCAD)] in addition to 15 healthy individuals as a control group were involved in this study. The studied individuals were subjected to complete history taking, thorough physical examination, electrocardiography, echocardiography and coronary angiography (for patients). Assessment of blood glucose level, lipid profile and creatine kinase (CK) was performed. Determination of hsCRP was done by nephlemetry, while C pneumoniae-, H pylori- and CMV-specific IgG antibodies was done by enzyme immunoassay. Results showed that the levels of cholesterol, triglycerides, LDL-c and hsCRP were significantly higher, while HDL-c was significantly lower among patients compared to that of the controls. A significantly (P<0.05) higher perecentage of patients had C pneumoniae and H pylori-specific IgG antibodies as compared to that of the controls. Higher percentage of patients had CMV-specific IgG antibody, however, there was no significant difference between the 2 groups. The levels of C pneumoniae and H pylori-specific IgG antibodies were significantly (P<0.001) higher among patients with CAD when compared to that of the controls. CMV-specific IgG level in patients was higher compared to that of the controls, however, the difference was not statistically significant. Among acute CAD patients, C pneumoniae-specific IgG was positively correlated with hsCRP (P<0.05), cholesterol (p<0.01) and HDL-c (P<0.05), while H pylori-specific IgG was positively correlated with triglyceride level (P<0.05). Among patients with CCAD, hsCRP was negatively correlated with HDL-c (P<0.05). There was no significant correlation between the levels of CMV-specific IgG and lipid profile or hsCRP. In conclusion, the level of C pneumoniae and H pylori-specific IgG antibodies are elevated among CAD patients and their presence was associated with development of the disease. They were significantly correlated to cholesterol level. Moreover, C pneumoniae-specific IgG was significantly correlated with hsCRP among ACAD patients, suggesting an important role of these organisms in the development of CAD by altering lipid profile and induction of inflammation.

A study of the role of IL-12 in pulmonary tuberculosis using the whole blood flowcytometry technique.

Pulmonary tuberculosis remains a major health problem. It is caused by Mycobacterium tuberculosis, which elicits a T-cell dependent immune response, initiated by monocytes through a large number of cytokines of which interleukin-12 is thought to play a critical role in initiation and regulation of T-helper (Th-1) like responses. To better understand the role of IL-12 in pulmonary tuberculosis patients, intracellular IL-12 in peripheral blood-derived monocytes was examined by flowcytometery. The percentage of monocytes producing IL-12 was measured after invitro stimulation of heparinized whole blood with mycobacterial protein antigens (culture filtrate). Of the 22 active tuberculosis patients, 17 were recent cases and 5 recurrent cases. Healthy controls were 14 individuals with detectable reaction to purified protein derivative (PPD+) and 14 without detectable reaction to PPD. The role of different factors affecting disease outcome such as treatment, age, gender, smoking, severity of disease and presence of other complications on the percentage of monocytes producing IL-12 was studied. Recurrent TB patients had a higher number of monocytes producing IL-12 in unstimulated cultures compared to other groups (P < 0.001). However, after in vitro stimulation there was a significant decrease in the number of monocytes producing IL-12 in recurrent TB patients as compared to recently diagnosed TB patients and healthy PPD+ individuals (P < 0.001). Antituberculosis chemotherapy was the only factor that had significant effect on the percentage of monocytes producing IL-12 (p < 0.05) while other studied factors did not show significant effect (p > 0.05). It is concluded that IL-12 plays a prominent regulatory role in tuberculosis.

Human natural killer T cells (NKT), NK and T cells in pulmonary tuberculosis: potential indicators for disease activity and prognosis.

One third of the world's population is infected with Mycobacterium tuberculosis (MTB). However, active disease can develop only in a small percentage, when the immunity is weakened. The acquired immune response to MTB is primarily mediated by T cells. Natural killer (NK) cells play a central role in innate immunity to microbial pathogens. Human NKT cells have characteristics of both T and NK cells and also exhibit antimycobacterial activity. This work aimed to enumerate T, NK and NKT cells in active pulmonary TB compared with healthy controls and to study the correlation between these cells with different factors affecting prognosis of pulmonary TB as disease severity, complications or associated diseases, antitubrculosis chemotherapy, and age & gender. Of the 22 active tuberculosis patients examined, 17 were recent cases and 5 recurrent. Healthy controls were divided into 14 individuals with detectable reaction to purified protein derivative (PPD+) and 14 individuals without detectable reaction to PPD-. The percentages of T, NK and NKT cells in erythrocyte-lysed whole blood samples were determined using flowcytometry. The percentage of NKT cells was significantly higher among the recently diagnosed MTB cases as compared with both PPD+ (P < 0.01) and PPD- (P < 0.01) healthy controls, while no significant difference could be found in the percentages of T or NK cells among these groups. However, comparing recurrent cases with recently diagnosed cases showed a significant difference only in the percentage of T cells (P < 0.01). There was also a significant difference in the percentage of T cells according to severity of disease (P < 0.01) and in the association of diabetes mellitus (P < 0.01). Age, gender and treatment with antituberculosis chemotherapy had no effect on the percentages of T, NK or NKT cells. It is concluded that T and NKT cells play an important role in immunity against TB. In active pulmonary tuberculosis, increased T cell count points to severity of the disease, while their reduced count predicts bad prognosis. Human NKT cell count is a marker of disease activity. Enumeration of these cells in peripheral blood can be used as a non-invasive prognostic indicator for patients with active pulmonary TB.