Central tolerance matters

In this issue of Immunity, Anderson et al. provide another clue to the riddle that is Aire--why do human beings and mice lacking Aire develop diffuse and pathogenic autoimmunity? They find that Aire influences central tolerance not only by promoting the expression of peripheral self-proteins in thymic medullary epithelial cells (MECs) but also by furnishing these cells with the apparatus for effective antigen presentation ().     

Anti-thyroid drugs and lymphocyte function. I. The in vitro effect on blastogenesis and suppressor cell activity

The in vitro effect of the anti-thyroid drugs (ATD), propylthiouracil (PTU) and methimazole (MMI) on blastogenesis of peripheral blood mononuclear cells (PBMC) from healthy subjects was studied in 72 hr PHA stimulated cultures. PTU in therapeutic concentrations (10 micrograms/ml) suppressed blastogenesis only when added at the last 18 hr of culture, while at 100 micrograms/ml significant suppression (25%) was recorded also for PTU present throughout culture. PTU had no cytotoxic effect on Raji cells as tested by 51Cr release assay and 3H-thymidine incorporation. Moreover, strong and irreversible suppression (33%) was induced in resting PBMC on 1 hr pre-incubation with PTU. These findings and the fact that suppression was recorded only in cultures exposed to suboptimal concentration of PHA (0.5 micrograms/ml) speak against a direct anti-metabolic effect. MMI in therapeutic concentration (1 microgram/ml) and tri-iodothyronine (T3) in pharmacological concentration (10(-7)M) were much less active. Suppression of blastogenesis by PTU appeared to be mediated through suppressor cell enhancement as indicated by: (a) the augmented blastogenesis following 24 hr pre-incubation, commonly ascribed to suppressor cell depletion, was blunted by pre-incubation with PTU; (b) mixing PTU pre-treated with untreated cells reduced the expected response to PHA and (c) PTU pre-incubated, mitomycin treated cells suppressed blastogenesis of autologous or allogeneic responder cells.     

Postkonvulsive Hyperammonämie

Zusammenfassung Bei 42 Kindern mit Krampfanfällen (grand mal) wurden Blutammoniakspiegelbestimmungen ausgeführt. Innerhalb der ersten 3 Std nach dem Krampfanfall waren die Spiegel ausnahmslos erhöht (23 Kinder). Zwischen 4 und 8 Std nach dem Anfall schwankten die Werte um den oberen Grenzbereich der Norm (6 Kinder). Die 24 Std nach Ablauf eines Krampfanfalles überprüften Ammoniakspiegel waren sämtlich normal (13 Kinder).Mit Unterstützung des Ministeriums für Soziales, Gesundheit und Sport Rheinland-Pfalz.     

Prostate specific antigen: not detectable despite tumor progression after radical prostatectomy

Prostate specific antigen was not detectable in 2 men with documented prostate cancer progression after radical prostatectomy. Possible explanations for prostate specific antigen remaining zero in these situations are discussed. We conclude that while monitoring prostate specific antigen is of great value in the followup of patients with prostatic cancer, it has not replaced more standard means of followup.     

Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8+ T cells

Adoptive T cell therapies (ACTs) hold great promise in cancer treatment, but low overall response rates in patients with solid tumors underscore remaining challenges in realizing the potential of this cellular immunotherapy approach. Promoting CD8⁺ T cell adaptation to tissue residency represents an underutilized but promising strategy to improve tumor-infiltrating lymphocyte (TIL) function. Here, we report that deletion of the HIF negative regulator von Hippel-Lindau (VHL) in CD8⁺ T cells induced HIF-1α/HIF-2α–dependent differentiation of tissue-resident memory–like (Trm-like) TILs in mouse models of malignancy. VHL-deficient TILs accumulated in tumors and exhibited a core Trm signature despite an exhaustion-associated phenotype, which led to retained polyfunctionality and response to αPD-1 immunotherapy, resulting in tumor eradication and protective tissue-resident memory. VHL deficiency similarly facilitated enhanced accumulation of chimeric antigen receptor (CAR) T cells with a Trm-like phenotype in tumors. Thus, HIF activity in CD8⁺ TILs promotes accumulation and antitumor activity, providing a new strategy to enhance the efficacy of ACTs.