Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion.

Regulatory T cell (Treg) therapy is a promising approach to improve outcomes in transplantation and autoimmunity. In conventional T cell therapy, chronic stimulation can result in poor in vivo function, a phenomenon termed exhaustion. Whether or not Tregs are also susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. To "benchmark" exhaustion in human Tregs, we used a method known to induce exhaustion in conventional T cells: expression of a tonic-signaling chimeric antigen receptor (TS-CAR). We found that TS-CAR-expressing Tregs rapidly acquired a phenotype that resembled exhaustion and had major changes in their transcriptome, metabolism, and epigenome. Similar to conventional T cells, TS-CAR Tregs upregulated expression of inhibitory receptors and transcription factors such as PD-1, TIM3, TOX and BLIMP1, and displayed a global increase in chromatin accessibility-enriched AP-1 family transcription factor binding sites. However, they also displayed Treg-specific changes such as high expression of 4-1BB, LAP, and GARP. DNA methylation analysis and comparison to a CD8+ T cell-based multipotency index showed that Tregs naturally exist in a relatively differentiated state, with further TS-CAR-induced changes. Functionally, TS-CAR Tregs remained stable and suppressive in vitro but were nonfunctional in vivo, as tested in a model of xenogeneic graft-versus-host disease. These data are the first comprehensive investigation of exhaustion in Tregs and reveal key similarities and differences with exhausted conventional T cells. The finding that human Tregs are susceptible to chronic stimulation-driven dysfunction has important implications for the design of CAR Treg adoptive immunotherapy strategies.

[Osteopoikilosos (author's transl)]. / Die Osteopoikilie

In Rumania, 26 cases of osteopoikilosis (20 males, 6 females) have been discovered. Five of these cases were familial (hereditary). Only 1 patient also had disseminated lenticular dermatofibrosis. All of the cases were discovered accidentally. All of the cases exibited the classic form of osteopoikilosis with stippling. Evaluation of the cases showed that various osteopoikilosis could be found in the same family and that probably the appearance of the condensation zones was related to the type of stress to which the bones are subjected (particularly pressure). Many cases show a tendency toward calcification in other tissues and not just in the bones (costal cartilage, periosteal reactions, lungs). In one case, a biopsy was made and a swelling of the trabeculae of the bone as well as cartilagenous proliferation was established.

[Dyschondroplasia (Ollier) (author's transl)]. / Dyschondroplasie Ollier

Over 20 years 5 patients with dyschondroplasia (Ollier) have been seen in the department for Orthopedics and Traumatology at Cluj-Napoca (Romania). Three were male, two female. 4 came from large families. First signs appeared gradually in 3, in 2 spontaneous fractures drew the attention to the disease. Radiographycally there were the typical chondromas with a strong tendency towards ossification in the adult. Shortening and deformity is proportional to the growth of the chondromas. The cause is unknown. In one case a chondroma became sarcomatous. One arm had to be exarticulated. This patient had no recurrence after 14 years.

Bone lesions in sarcoidosis.

Roentgenographs from hands and feet have been made from 97 out of 162 patients suffering from a gangliopulmonary sarcoidosis. In 34 patients bone alterations have been stated. In cases of an advanced gangliopulmonary sarcoidosis the bone alterations were more frequent. In 23 cases the findings showed osteolytic characteristics. In 4 of the cases they consisted in circumscribed foci of condensation. In 7 cases osteolyses and condensations appeared in combination with one another. Up to now there are no data in literature about bone condensations in case of a sarcoidosis. Their classification into the aspect of this disease is recommended with due reserve.

[A case of Maffucci-Kast syndrome (author's transl)]. / Das Maffucci-Kast-Syndrom

A 40-year-old man showed the typical cardinal signs of Maffucci-Kast syndrome: largely one-sided bony chondromatosis and tuberous dermal angiomata. In addition there were pigmented spots in the skin, moderate hypertrophy of the extremities most involved (left hand and foot) and hypoplasia of the skeleton in these parts.

[Surgical or isotopic synovectomy?]. / Sinovectomie chirurgicala.......sau izotopica?

A total of 40 patients were treated, suffering with chronic rheumatic arthropathies of the knee, by synoviorthesis with 198Au. The patients were followed for more than 3 years. Good results were obtained in 90% of the cases. The advantages are considered of the isotopic synovectomy (synoviorthesis with 198Au), as compared with surgical synovectomy. Isotopic synoviorthesis is a non-surgical procedure of destruction-reconstruction of the pathological synovial. The method has a local and a general immuno-depressing effect (reduction of the abnormal protein generation, of the chondrolytic activity of the synovial and of the permeability disturbances from various chronic exsudates in the knee articulation). The knee articulation is particularly well suited for the use of these therapeutical method. The secondary effects and the organism irradiation are minimal.