Histone/protein deacetylase inhibitor therapy for enhancement of Foxp3+ T-regulatory cell function posttransplantation.

T-regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these responses involves changes in posttranslational modifications (PTMs) of histones and many nonhistone proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination, and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini-review focuses on recent data concerning the roles that histone/protein deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg-dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform-selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients.

Blunted expression of miR-199a-5p in regulatory T cells of patients with chronic obstructive pulmonary disease compared to unaffected smokers.

Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal regulatory T cell (T(reg)) response and increases in T helper type 1 (Th1) and Th17 cell responses. It is unclear if dysregulation of microRNAs (miRNA) within T(reg) cells contributes to the abnormal inflammatory response in COPD. In this study, we aimed to compare the miRNA profile of COPD T(reg) cells with that of healthy controls and to explore the function of differentially expressed miRNAs. We first obtained T(reg) and T effector cells (Teff ) from peripheral blood of non-smokers, unaffected current smokers and COPD current smokers. Then, we assessed their miRNA expression by microarray analysis followed by real-time reverse transcription-polymerase chain reaction (RT-PCR) validation of particular miRNAs. Six and 96 miRNAs were expressed differentially in COPD T(reg) cells versus T(reg) cells of healthy non-smokers and healthy smokers, whereas no differences were found in miRNA expression in T(eff) cells. We found that miR-199a-5p was repressed by approximately fourfold in T(reg) cells of COPD patients compared to healthy smokers (P < 0·05). In addition, miR-199a-5p was over-expressed in T(reg) cells compared to Teff cells (P < 0·001) and had significant over-representation of its target genes in the T(reg) transcriptome, being associated with the transforming growth factor (TGF)-ß activation pathway (P < 0·01). We also confirmed the function of miR-199a5p in an in-vitro loss-of-function cell model running TaqMan® arrays of the human TGF-ß pathway. These findings suggest that the abnormal repression of miR-199a-5p in patients with COPD compared to unaffected smokers may be involved in modulating the adaptive immune balance in favour of a Th1 and Th17 response.

Targeting sirtuin-1 alleviates experimental autoimmune colitis by induction of Foxp3+ T-regulatory cells.

Induced Forkhead box P3-positive (Foxp3(+)) T-regulatory cells (iTregs) are essential to gastrointestinal immune homeostasis, and loss of the ability to develop iTregs may lead to autoimmune colitis. We previously showed a role for sirtuin-1 (Sirt1) in control of Treg function and hypothesized that targeting of Sirt1 might enhance iTreg development and thereby represent a potential therapy for inflammatory bowel disease (IBD). We adoptively transferred CD4(+)CD25(-)Foxp3(-) T effector (TE) cells from wild-type (WT) (C57BL/6) or fl-Sirt1/CD4cre mice into B6/Rag1(-/-) mice and monitored the mice until they lost 10-15% of their weight. Adoptive transfer of TE cells lacking Sirt1 to B6/Rag1(-/-) mice resulted in a 2.8-fold increase in iTreg formation compared with mice receiving WT TE cells and correlated with attenuated colitis and reduced weight loss (1.04±1.4% vs. 13.97±2.2%, respectively, P<0.001). In a second model of IBD, we used pharmacologic Sirt1 targeting of mice receiving multiple cycles of dextran sodium sulfate (DSS) in their drinking water, alternated with fresh water. Likewise, WT mice receiving cyclic DSS and a Sirt1 inhibitor, EX-527, had reduced weight loss (5.8±5.9% vs. 13.2±6.9%, respectively, P=0.03) and increased iTreg formation compared with controls. Sirt1 appears a promising target for pharmacologic therapy of IBD as a result of promoting iTreg development.

Differing effects of rapamycin or calcineurin inhibitor on T-regulatory cells in pediatric liver and kidney transplant recipients.

In a cross-sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T-regulatory (Treg) cells from children with stable liver (n = 53) or kidney (n = 9) allografts several years posttransplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg-specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. Forty-eight patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r =-0.424, p = 0.017). CNI levels inversely correlated with Treg number (r =-0.371, p = 0.026), and positively correlated with CD127+ expression by Tregs (r = 0.437, p = 0.023). Patients with CNI levels >3.6 ng/mL had weaker Treg function than those with levels <3.6 ng/mL, whereas rapamycin therapy positively correlated with Treg numbers (r = 0.628, p = 0.029) and their expression of CTLA4 (r = 0.726, p = 0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long-term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.

[Rehabilitation potential of disabled persons with consequences of cerebral stroke and effects of factors of the organization of rehabilitation assistance].

The authors demonstrated the possibility for the practical use of the index "Rehabilitation Potential" in the evaluation of the degree of restoration of neurological deficit developed due to cerebral stroke. The most significant factors characterizing the organization and implementation of rehabilitation measures in different periods of stroke and the effect of these factors on the level of rehabilitation potential of disabled persons with consequences of stroke are specified. It has been shown that the perfect organization of restorative treatment has a positive effect on the level of rehabilitation potential of disabled persons.

[Quantitative criteria of a rhinocytogram of healthy subjects]. / Kolichestvennye kriterii rinotsitogrammy zdorovogo cheloveka.

Presents qualitative and quantitative characteristics of normal rhinocytograms obtained by cytologic investigations of smears impressions from the surface of the anterior portion of the inferior turbinate bone and processing of the results by variation statistics methods. Actually only solitary scales and superficial cells of multilayer squamous epithelium and small groups of ciliary epithelium cells may be reliably present in a normal rhinocytogram of man.

[The physicochemical and biological properties of the bovine hemoglobin polymer]. / Izuchenie fiziko-khimicheskikh i riada biologicheskikh svoistv polimera gemoglobina byka.

A study was made of bovine hemoglobin polymer obtained by a new method: intraerythrocytic polymerization of hemoglobin followed by isolation of hemoglobin polymer. The polymer obtained had weighted mean and numerical average molecular mass of 388 kD and 134 kD, respectively, P 32 mm Hg, arteriovenous difference 5.1 vol%, Hill's coefficient 2.14, oxygen output rate constant 55 sec, and it retained its activity during long-term storage. Its solution in a concentration of 9-10 g/dl has a viscosity of 2.34, and an oncotic pressure of 240 mm water. Bovine hemoglobin polymer is nontoxic and capable of long-term circulation in the blood. Its safety and clinical effectiveness should be studied in an extended biological experiment.

[The results of the dynamic observation of patients with reactive Yersinia arthritis]. / Rezul'taty dinamicheskogo nabliudeniia bol'nykh reaktivnym iersinioznym artritom.

As many as 50 patients with reactive Yersinia arthritis were followed up. There were 4 men and 46 women. The mean age of the patients was 31.1 yr. The mean follow-up period was 30.8 months. In 72% of the cases, the disease was preceded by diarrhea. During the first examination, mono-oligoarthritis was detected in 78% of the patients. Extra-articular alterations (damage of muscles, ligaments, heart, skin changes, etc) were also recorded. The results of bacteriological analyses were positive in 22 out of the 50 patients. In 16 persons, Yersinia might be cultivated from the different biological media: blood, feces, urine, fauces, and synovial fluid. In 47 persons, arthritis took a chronic course. Persistence of antibodies of the types 03 and 09 seen for many years merits attention. Monoclonal anti-Yersinia antibodies were also detectable repeatedly. In 8 patients, in whom Yersinia were cultivated from a lot of the biological media, the disease ran an especially grave course. The role of circulating specific antibodies in patients with Yersinia arthritis and the trigger role they may play in the development of RA and ankylosing spondylarthritis requires further discussion.

[Clinico-immunologic characteristics of complicated and uncomplicated yersiniosis]. / Kliniko-immunologicheskaia kharakteristika oslozhennogo i neoslozhnennogo iersinioza.

Asymmetric affection of the major lower limb joints is a characteristic feature of the joint syndrome in yersiniosis-associated arthritis. The sacroiliac articulations are frequently (47% cases) involved. In addition, yersiniosis-associated arthritis concurs with the signs and symptoms of systemic disease--gastroenterocolitis, myocardiopathy and myocarditis, erythema nodosum, hepatitis, urethritis, conjunctivitis, myositis and myalgia, enteropathy; changes in the CNS typical for the astheno-neurotic syndrome are frequently present. Comparison of the immunological assay data in complicated and uncomplicated yersiniosis shows equally high levels of IgG and CIC. High anti-DNA antibody titres are more frequently found in the serum of uncomplicated yersiniosis patients. ELISA quantitation of specific IgA, IgM, and IgG class antibodies in yersiniosis-associated arthritis patients demonstrated persistence of all the three antibody classes or of IgA-IgG combination in cases with most severe of the joint syndrome. In the presence of cardiac disease, patients were found to have high titres of antibodies reactive with the cardiac interstitial tissue, while in authentically diagnosed myocarditis cases with the sarcolemma. The investigation findings strongly suggest a high degree of involvement of immune and autoimmune processes in the pathogenesis of arthritides secondary to Yersinia infection.

[Rehabilitation of patients with gout during outpatient follow-up]. / Reabilitatsiia bol'nykh podagroi pri dispansernom nabliudenii.

The authors presented the results of a 5-year follow-up of 50 gout patients who had been regularly (no less than 3-4 times a year) examined in outpatient clinics. Dispensary examinations of the patients resulted in a decrease in the level of uric acid and in the number of exacerbations of gouty arthritis, the reduction of the sizes of tophi or their disappearance. Regular examination and ultrasonic investigation made it possible to prevent in some cases attacks of urolithiasis, and to reduce 4-fold a disability time-period and to preserve working capacity in 96% of the patients. The study showed that in most of the patients with essential hypertension and coronary heart disease arterial pressure got stable and the number of angina attacks was on a decrease. The data obtained indicated a high efficacy and appropriateness of combined rehabilitation activities in gout patients.

[Echodiagnosis of the kidney lesion in gout]. / Ekhodiagnostika porazheniia pochek pri podagre.

An echographic study of the kidneys was performed in 24 men with proved gout aged 40 to 50 and a disease duration of 10-20 yrs. On the basis of case history data urolithiasis was noted in 4 patients, whereas by echodiagnosis it was found in 12. Cysts were detected in 6 patients with gout complicated by urolithiasis and in 1 patient without it. Echoroentgenography was shown to be a highly informative method in the diagnosis of urolithiasis and cystic regeneration of the kidneys opening up prospects for earlier treatment of complications in gout.

[Evolution of seronegative arthritis]. / Evoliutsiia seronegativnogo artrita.

The paper is concerned with the results of a follow up of 67 patients with seronegative arthritis. The average duration of observation was 7.6 yrs. Diagnoses in 4 patients were established on a repeated clinicolaboratory and x-ray study: ankylosing spondylitis, Reiter's syndrome, Yersinia arthritis and gonorrheal arthritis. A picture of seropositive rheumatoid arthritis was noted in 16 patients (24%). In 47 patients arthritis remained seronegative. Of them in 30 patients a course of disease did not differ from that of seropositive rheumatoid arthritis. Considerable progression of disease was noted at the acute onset of disease with multiple involvement of the joints and a high inflammatory and immunological activity of a process. A morphological investigation of the synovial bioptates in 20 patients did not reveal a classical picture of rheumatoid synovitis even in a prolonged course of seronegative rheumatoid arthritis. The authors defined two variants of morphological changes in the synovial tissue in this group corresponding to a benign and progressive course of seronegative RA.

[Morphology of the intranuclear inclusions in Entamoeba histolytica trophozoites]. / Morfologiia vnutriiadernykh vkliuchenii trofozoitov Entamoeba histolytica.

Electron microscope studies of spherical intranuclear inclusions (II) of Entamoeba histolytica trophozoites of two strains, which were maintained in polyxenous culture for different periods of time, were carried out. Data on the number of II in different individuals and in different strains are given. The structure of II whose external layer consists of electron dense material and resembles morphologically peripheral chromatin of the ameba's nucleus, an analogy of nucleolus chromatin of cells of other eucariots, is considered. Inside this layer some II have annular filaments about 9 nm thick rolled up spherically around the central zone of II. Comparison of results obtained and literary data suggests that the dynamic structure of II in question reflects a number of biosynthetic processes on the basis of annular extrachromosomal DNA of exogenic origin.

Predicting the outcome of rheumatoid arthritis. A Soviet-Finnish co-operative study.

The prognostically important signs and symptoms in the early stage of rheumatoid arthritis were studied in 136 patients selected and treated in Moscow and in 139 patients in Heinola, Finland. The follow-up time was 3 years. The outcome was poor in patients with early signs of radiological destruction in the joints, with rheumatoid factor in serum, with early functional disability or deficient flexion of the fingers, with multiple affliction of the finger, metatarsophalangeal or wrist joints, with marked morning stiffness, and with CRP in the serum. The age of the patients did not influence the outcome in Moscow, whereas in Heinola the mean age was higher in patients with a poor outcome. Despite the marked differences in the therapeutic methods and the outcome for patients, the prognostically important signs and symptoms were very similar in both centres.