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Natural killer (NK) cells induce apoptosis in infected and transformed cells and are important producers of immunoregulatory cytokines. Therefore, they operate under low oxygen conditions (hypoxia) in inflammatory and tumor environments. In vitro studies of NK cells are, however, commonly performed in ambient air (normoxia). We used global gene expression profiling to evaluate changes in transcriptional pathways in primary human NK cells following short term culture under hypoxia compared with normoxia and in response to interleukin 15 (IL- 15) priming using a 2 × 2 factorial design. The largest contrasts observed were priming dependences for associations between hypoxia and the hypoxia-inducible factor (Hif) 1 signaling and glycolysis pathways. RT-PCR confirmed positive synergistic hypoxia/IL-15 interactions for genes of key regulatory and metabolic enzymes. IL-15 primes NK cells for effector functions, which were recently demonstrated to depend on glycolytic switching. We did not, however, observe important increases in glycolytic flux through hypoxia and priming alone. Chemical Hif-1α inhibition suggested equal importance of this transcription factor for glycolysis and energy production under normoxia and hypoxia. Hypoxia promoted secretion of CC chemokines Ccl3/4/5 and macrophage migration inhibitory factor. Unexpectedly, hypoxia also stimulated migration of NK cells through the extracellular matrix and shifted amounts of susceptible leukemia target cells toward late apoptosis in a cell killing assay. We conclude that short term hypoxia supports these activities by positively interacting with NK cell priming at the level of glycolytic gene transcription. Hypoxic conditioning of NK cells may thus benefit their use in cell-based immunotherapy of cancer. [ABSTRACT FROM AUTHOR]

High serum sCD30 levels are associated with inflammatory disorders and poor outcome in renal transplantation. The contribution to these phenomena of transcripts and proteins related to CD30-activation and -cleavage is unknown. We assessed in peripheral blood of end-stage renal disease patients (ESRDP) transcripts of CD30-activation proteins CD30 and CD30L, CD30-cleavage proteins ADAM10 and ADAM17, and Th1- and Th2-type immunity-related factors t-bet and GATA3. Additionally, we evaluated the same transcripts and release of sCD30 and 32 cytokines after allogeneic and polyclonal T-cell activation. In peripheral blood, ESRDP showed increased levels of t-bet and GATA3 transcripts compared to healthy controls (HC) (both P < 0.01) whereas levels of CD30 , CD30L , ADAM10 and ADAM17 transcripts were similar. Polyclonal and allogeneic stimulation induced higher levels of CD30 transcripts in ESRDP than in HC (both P < 0.001). Principal component analysis (PCA) in allogeneic cultures of ESRDP identified two correlation clusters, one consisting of sCD30, the Th-1 cytokine IFN-γ, MIP-1α, RANTES, sIL-2Rα, MIP-1β, TNF-β, MDC, GM-CSF and IL-5, and another one consisting of CD30 and t-bet transcripts, IL-13 and proinflammatory proteins IP-10, IL-8, IL-1Rα and MCP-1. Reflecting an activated immune state, ESRDP exhibited after allostimulation upregulation of CD30 transcripts in T cells, which was associated with Th1 and proinflammatory responses. [ABSTRACT FROM AUTHOR]

Abstract: High serum levels of soluble CD30 (sCD30) are associated with poor renal allograft survival, and regulatory T cells (Tregs) influence allograft survival depending on CD30 signaling. However, how sCD30 modulates alloimmune responses remains poorly understood. We measured the level of Tregs and sCD30 in patients with end-stage renal failure (ESRF) and analyzed whether allo- or polyclonal stimulation of the patients’ T cells results in the expression and release of CD30. ESRF patients showed increased serum sCD30 levels and lower percentages of circulating Tregs as compared to healthy controls (HC) (p <0.001 and 0.024). Polyclonal and allogeneic stimulation resulted in higher expression of CD30, and after polyclonal stimulation, ESRF patients showed higher percentages of CD30-expressing T cells than HC (p <0.001). Compared to autologous stimulation, allogeneic stimulation induced significantly higher expression of CD30 on T cells of ESRF patients only. After polyclonal as well as allogeneic stimulation, an increased sCD30 content was found in culture supernatants of both ESRF patients and HC (p <0.001). Together with decreased Tregs, high serum sCD30 and increased induction of CD30 on T cells after polyclonal stimulation may explain exacerbated alloimmune responses and poor allograft survival in ESRF patients in whom immunosuppression is not able to control the alloimmune response. [Copyright &y& Elsevier]