Targeted IL‐4 therapy synergizes with dexamethasone to induce a state of tolerance by promoting Treg cells and macrophages in mice with arthritis

F8‐IL‐4 is a recently developed immunocytokine that delivers IL‐4 to sites of inflammation by targeting the neovasculature. We previously reported that F8‐IL‐4, in combination with dexamethasone (DXM), provides a durable therapy in mice with collagen‐induced arthritis (CIA). Therefore, the objective of this study was to identify the mechanism by which IL‐4 and DXM combination therapy provides long‐lasting disease remission. F8‐IL‐4 alone attenuated inflammation in CIA and this was associated with increased T_H2 and decreased T_H17 cell numbers in the joints. Similarly, DXM alone had an antiinflammatory effect associated with lower T_H17 cell numbers. In both cases, these therapeutic benefits were reversed once treatment was stopped. On the other hand, combination therapy with F8‐IL‐4 plus DXM led to a synergistic increase in the percentage of regulatory T (Treg) cells and antiinflammatory macrophages in the arthritic joint and spleen as well as IL‐10 levels in serum and spleen. The net result of this was a more pronounced attenuation of inflammation and, more importantly, protection from arthritis relapse post therapy retraction. In conclusion, F8‐IL‐4 plus DXM is a durable treatment for arthritis that acts by promoting Treg cells in a synergistic manner, and by producing a sustained increase in antiinflammatory macrophages.     

Hla—dr antigens and anticardiolipin antibodies in northern italian systemic lupus erythematosus patients

Eighty systemic lupus erythematosus (SLE) patients attending 3 clinical centers were evaluated immunologically and immunogenetically. No HLA class I1 antigens were found to be significantly associated with SLE in these patients. A highly significant (P = 6.17 × 1o⁻⁷) association was observed between anticardiolipin antibodies and DR7. A lesser association (P < 0.025) was also observed between DR2 and/or DR3 and anti—Ro (SS-A) antibodies. No relationship was found between any DR antigen and anti-Sm/RNP, antidouble-stranded DNA, or anti—La (SS-B) antibodies.     

Donor-Model for End-Stage Liver Disease and donor-recipient matching in liver transplantation

Background

The product between donor (D) age and recipient (R) Model for End-Stage Liver Disease (MELD) score at the moment of liver transplantation (LT) has been proposed as a potential D-R matching tool to reduce the risk of “futile” LT from using the MELD score as the main allocation tool. The aim of this study was to evaluate the prognostic ability of D-MELD among a cohort of Italian patients already selected for LT on the basis of a D-R matching philosophy.

Methods

We studied 303 consecutive adult patients undergoing first LT for chronic liver diseases with available D-MELD at the moment of LT from 2003 to 2009. Optimal donors were assigned to more severe cirrhotic patients (MELD ≥20); suboptimal organs were allocated to patients with hepatocellular carcinoma (HCC) not responsive to bridging therapies (specific priority score) or other exceptions with MELD <20. A suboptimal donor had age >70 years, severe steatosis by ultrasound, and/or body mass index >30 kg/m², partial liver, or hepatitis C (HCV) or B virus positivity.

Results

Characteristics of the study group were a median age of 55 years (range, 27-68 years), HCV positivity in 164 patients (54%), HCC in 134 patients (44%), partial liver use in 25 (8%), MELD 15 (range, 6-40), D-age of 56 years (range, 18-87 years), and median D-MELD score 826 (range, 126-2,988). Overall graft survival was 84%, 79%, and 77% at 1, 3, and 5 years after LT, respectively. Logistic regression did not show a significant correlation between graft failure and D-MELD score in the absence of a significant D-MELD cutoff. Cox regression with D-MELD as the continuous variable showed a hazard ratio (HR) of 0.99 (95% confidence interval [CI], 0.99-1.00; P = NS); and with D-MELD as a dichotomic variable (≥0 to <1,600) an HR of 0.98 (95% CI, 0.63-1.77; P = NS).

Conclusion

The prognostic ability of D-MELD fails in OLT centers that use a more complex D-R matching policy.     

White-line: A new finding in laryngopharyngeal reflux objective evaluation

Laryngopharyngeal reflux (LPR) indicates the reflux-induced extra-esophageal disorders. LPR and gastroesophageal reflux disease (GERD) occur by the same mechanism: the escape of gastric contents into the esophagus and beyond. However, the classic GERD symptoms are not typical in LPR disease, which can cause a lot of symptoms none of which is specific, making the diagnosis often elusive. The protective mechanisms present in the esophagus are entirely lacking in the larynx, and more generally in upper aerodigestive tract, making them particularly vulnerable to injury from acidic gastric contents. Since gastric acid backflow can affect supraesophageal structures, even in the absence of heartburn or regurgitation symptoms, an early diagnosis is important to prevent the onset of histological modifications in the supraesophageal mucosa.     

Effects of leptin and leptin fragments on steroid secretion and proliferative activity of regenerating rat adrenal cortex

Leptin, an adipose tissue-secreted hormone, acts via several isoforms of specific receptors (Ob-Rs), which may variously interact with the native leptin molecule and its fragments. Evidence has been provided that leptin affects rat adrenal functions, but the results were rather conflicting depending on the experimental condition examined (e.g. regenerating vs. mature or immature adrenal gland). Hence, we investigated the effects of three subcutaneous injections of murine leptin(1-147) and several leptin fragments (3 nmol/100 g body weight; 28, 16 and 4 h before the sacrifice) on the secretory activity and growth of regenerating rat adrenal cortex. The following leptin fragments were tested: murine leptin(116-130), and human leptin fragments 150-167, 138-167, 93-105, 22-56 and [Tyr]26-39. Leptin(1-147) enhanced plasma concentration of both aldosterone and corticosterone. The blood level of aldosterone was raised by leptin(116-130), leptin(138-167) and leptin(93-105), and that of corticosterone by leptin(93-105) and Tyr-leptin(26-39). Metaphase index (stachmokinetic method with vincristine) was unaffected by leptin(1-147), and lowered by leptin(116-130), leptin(150-167) and leptin(138-167). Collectively, our findings allow us to conclude that leptin and leptin fragments enhance the secretory activity and inhibit the growth of regenerating rat adrenal cortex, the biological activity of leptin being located in the C-terminal segment of its molecule.     

Chemokine production by natural killer cells from nonagenarians

In this study we investigated whether purified NK cells, derived from a group of nonagenarian healthy subjects, were able to produce the chemokines MIP-1alpha, RANTES and IL-8, and also characterized the effect of IL-12 or IL-2 immunomodulatory cytokines (that are among the most effective inducers of NK lytic activity and soluble factor secretion) on the induction, in vitro, of these chemokines and on the modulation of the corresponding receptors. This study provides evidence that human NK cells from healthy subjects over 90 years old retain the ability to synthesize MIP-1alpha, Rantes and IL-8 chemotactic cytokines, that NK cells isolated from these subjects can be activated to significantly up-regulate the production of these chemokines in response to stimulation by IL-12 or IL-2 cytokines (even though production remains lower than that observed in young subjects), and that NK cells express the corresponding chemokine receptors.