Mouse models for the study of fate and function of innate lymphoid cells

Natural killer (NK) cells and lymphoid tissue inducer (LTi) cells were discovered more than 40 and 20 years ago, respectively. These two cell types were initially studied for their unique functions in the elimination of infected or transformed cells, and in the development of lymphoid tissues. It took an additional 10 years to realize that NK cells and LTi cells were members of a larger family of innate lymphoid cells (ILCs), whose phenotypes and functions mirror those of T cells. Many mouse models have since been developed to identify and isolate ILCs, map their developmental pathways and characterize their functions. Because of the similarity between ILCs and T cells, this exploration remains a challenge. In spite of this, a broad range of mouse models available to researchers has lead to significant progress in untangling the unique roles of ILCs early in defense, regulation of adaptive immunity and homeostasis. Here, we review these mouse models, and discuss their strengths and limitations.     

Cyto‐histological correlation of Xp11.2 translocation/TFE3 gene fusion associated renal cell carcinoma: Report of a case with review of literature

The MiT family translocation renal cell carcinomas (RCCs) are relatively rare in comparison to the conventional RCC. The cytologic features overlap with conventional clear cell RCC and papillary RCCs, thereby making the diagnosis extremely challenging. Here, we describe a case of TFE3 translocation associated RCC in a 58‐year‐old patient, with emphasis on cytomorphologic features and clues toward this diagnostic entity. Correlating the cytohistologic findings and review of touch imprints revealed that presence of hyaline nodules resembling leisegang rings and psammoma bodies in cytologic smears from kidney tumors serve as an important clue in raising a suspicion for the diagnosis of MiT family translocation RCCs.     

Development of a BiTE®-mediated CD8+ cytotoxic T-lymphocyte activity assay to assess immunomodulatory potential of drug candidates in Cynomolgus macaque

The immunotoxic potential of drug candidates is assessed through the examination of results from a variety of studies and endpoints. While the functional assessment of CD8⁺ cytotoxic T-lymphocytes (CTL) is well-characterized in the clinic, the lack of a robust macaque CTL functional assay has been an important hurdle in evaluating and accurately quantifying cell-mediated CD8⁺ T-cell effector responses in the nonclinical setting. This paper describes the development of an assay to measure CTL activity in peripheral blood mononuclear cells (PBMC) isolated from Cynomolgus macaques. A human EGFR/CD3 Bispecific T-cell Engager (BiTE^®) was used to mount a robust CD8⁺ T-cell response in the presence of target-expressing cells. Upon target engagement, degranulation of CD107a and production of interferon (IFN)-γ both reliably indicated a robust functional response in CD8⁺ T-cells. The BiTE^®-mediated stimulation method proved to be favorable when compared to other methods of stimulation in the absence of target cells. These studies demonstrated acceptable longitudinal variability of the functional assay and sensitivity to dexamethasone-mediated immunosuppression. Taken together, the results indicated an assay leveraging CD3-bispecific antibodies and target-expressing cells can provide a robust approach to the in vitro or ex vivo assessment of CTL function in Cynomolgus macaques. Because the impairment of CTL activity by immunomodulators is recognized to be an important contributor to decreased antiviral defense and increased carcinogenicity risk, we believe that this novel assay to be a valuable addition to the immunotoxicology assessment of therapeutic drug candidates.     

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology. In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients. Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.     

Peroneus longus tendon transfer; prospective study of treatment outcome of recurrent fixed clubfoot deformities in children after failed surgical treatment

BackgroundIn childhood, for flexible clubfoot deformity, the transfer of the tendon of the tibialis anterior muscle is widely used. In contrast, extensive surgical procedures are required for fixed clubfoot deformities.MethodsWe describe the peroneus longus tendon transfer to the peroneus brevis tendon, additionally to full surgical release, in cases of recurrent fixed clubfoot deformities. The purpose of this surgical technique was to restore and maintain the dynamic balance of foot inversion-eversion during the gait cycle by augmenting the muscular strength of the weak peroneus brevis tendon. We report the prospective study of treatment outcome of twenty recurrent fixed clubfoot deformities in twelve children (20 feet) after failed surgical treatment they had. Anteroposterior and lateral radiographs under full-body weight-bearing and the AOFAS score pre-and postoperatively were used in all patients. For the estimation of the severity of the recurrent clubfoot deformity in each child and to increase the credibility of the AOFAS rating scale, we additionally used a clubfoot sheet score preoperatively and postoperatively (maximum score 100 points for normal foot appearance clinically and radiologically).ResultsThe mean age at surgery was 6,85 (±1,81; 5–11) years. The mean follow-up time was 5,4 (±1,7; 2–8) years. The mean AOFAS ankle-hindfoot rating score increased from 69,85 (±9,51; 53–82) points preoperatively to 94,4 (±2,43; 91–97) points postoperatively. The mean clubfoot sheet rating score increased from 43,00 (±12,18; 15–55) points, preoperatively to 90,0 (±4,58; 80–95) points postoperatively. The two-tailed p-value was < 0,0001.ConclusionsThe transfer of the peroneus longus tendon to the peroneus brevis tendon is a minimal surgical procedure that acts collaboratively in maintaining the correction of foot deformity, achieved by the complete surgical release. Level of Evidence: IV.