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Key Points IL-6 is dysregulated after experimental allogeneic SCT and promotes alloantigen-dependent Th17 expansion within the lung. IL-6 is dysregulated in patients with IPS after clinical allogeneic SCT.

Although the effects of type II-IFN (IFN-␥) on GVHD and leukemia relapse are well studied, the effects of type I-interferon (type I-IFN, IFN-␣/␤) remain unclear. We investigated this using type I-IFN receptordeficient mice and exogenous IFN-␣ administration in established models of GVHD and GVL. Type I-IFN signaling in host tissue prevented severe colontargeted GVHD in CD4-dependent models of GVHD directed toward either major histocompatibility antigens or multiple minor histocompatibility antigens. This protection was the result of suppression of donor CD4 ؉ T-cell proliferation and differentiation. Studies in chimeric recipients demonstrated this was due to type I-IFN signaling in hematopoietic tissue. Consistent with this finding, administration of IFN-␣ during conditioning inhibited donor CD4 ؉ proliferation and differentiation. In contrast, CD8-dependent GVHD and GVL effects were enhanced when type I-IFN signaling was intact in the host or donor, respectively. This finding reflected the ability of type I-IFN to both sensitize host target tissue/leukemia to cell-mediated cytotoxicity and augment donor CTL function. These data confirm that type I-IFN plays an important role in defining the balance of GVHD and GVL responses and suggests that administration of the cytokine after BM transplantation could be studied prospectively in patients at high risk of relapse. (Blood. 2011;118(12):3399-3409) IntroductionAlthough allogeneic BM transplantation is curative therapy for a majority of hematologic malignancies, its application has been limited by the development of GVHD. GVHD is the result of immunologic damage to the host tissue by alloreactive T cells from the incoming donor graft. Unfortunately, the development of detrimental GVHD is closely intertwined with therapeutic GVL responses. GVL responses are important for eradication of residual host malignancy and are primarily mediated by alloreactive donor T and natural killer (NK) cells. Therapeutic approaches to separate these phenomena are urgently needed.The IFNs were first discovered as a result of their capacity to confer cell resistance to viral infection. 1 There are 2 distinct IFN types, type I and type II, and although both groups induce antiviral defense mechanisms in cells, primarily by limiting replication, they exhibit distinct immunologic properties. After allograft rejection, it is well established that the type II-IFN, IFN-␥, is a dominant Th1 cytokine, exerting pleotropic effects on both hematopoietic and nonhematopoietic cells. Importantly, IFN-␥ has differential effects on both donor and host tissue, with a protective role dominating within GVHD of the lung and pathogenic effects dominating in the gastrointestinal tract. [2][3][4] In addition, the cellular subsets producing IFN␥ and the timing of production may also impact the effect of the cytokine after BM transplantation. 5 In contrast, the role of type I-IFN after BM transplantation remains largely unknown.All type I-IFNs act through the same receptor, which is composed of 2 subunits, IFNAR...

Daclizumab, a humanized antibody directed against the a -chain of the interleukin-2 receptor (CD25), has shown efficacy in the prevention of acute rejection following organ transplantation. However, anti-CD25 therapy can be expected to affect not only alloreactive effector T cells, but also CD4 + CD25 + regulatory T (Treg) cells that are shown to play an important role in the induction of transplantation tolerance. Therefore, the size and function of the Treg pool in human renal allograft recipients after single-dose daclizumab administration was investigated in this study. Approximately 8 weeks after administration, daclizumab was cleared from the circulation and the Treg population then present appeared not different from that observed before transplantation. Functional analysis revealed that the Treg possessed a normal capacity to suppress mixed lymphocyte reactions in vitro. These data indicate that after daclizumab therapy a Treg population, normal in number and function, is present in the peripheral blood of renal transplant recipients.

BackgroundTransplant patients would benefit from reduction of immunosuppression providing that graft rejection is prevented. We have evaluated a number of immunological markers in blood of patients in whom tacrolimus was withdrawn after renal transplantation. The alloreactive precursor frequency of CD4+ and CD8+ T cells, the frequency of T cell subsets and the functional capacity of CD4+CD25+FoxP3+ regulatory T cells (Treg) were analyzed before transplantation and before tacrolimus reduction. In a case-control design, the results were compared between patients with (n = 15) and without (n = 28) acute rejection after tacrolimus withdrawal.Principal FindingsPrior to tacrolimus reduction, the ratio between memory CD8+ T cells and Treg was higher in rejectors compared to non-rejectors. Rejectors also had a higher ratio between memory CD4+ T cells and Treg, and ratios <20 were only observed in non-rejectors. Between the time of transplantation and the start of tacrolimus withdrawal, an increase in naive T cell frequencies and a reciprocal decrease of effector T cell percentages was observed in rejectors. The proportion of Treg within the CD4+ T cells decreased after transplantation, but anti-donor regulatory capacity of Treg remained unaltered in rejectors and non-rejectors.ConclusionsImmunological monitoring revealed an association between acute rejection following the withdrawal of tacrolimus and 1) the ratio of memory T cells and Treg prior to the start of tacrolimus reduction, and 2) changes in the distribution of naive, effector and memory T cells over time. Combination of these two biomarkers allowed highly specific identification of patients in whom immunosuppression could be safely reduced.

The prevalence of acute respiratory infections and their impact on quality of life underlies the need for efficacious solutions that are safe, sustainable and economically viable. Polysaccharides in several (traditional) plant extracts have been shown to be immunostimulatory, and some studies suggest beneficial effects against respiratory infections. The aim of this study was to (i) identify the active polysaccharide constituents from affordable and renewable crops (bell pepper and carrot) using activity-guided fractionation, (ii) evaluate in vitro effects on innate immune responses (phagocytosis and cytokine secretion), microbiota modulation and production of short chain fatty acids, followed by (iii) the evaluation of effects of a bell pepper extract enriched for the active component in a human proof of concept study. We identified rhamnogalacturonan-I (RG-I) as the nutricophore responsible for the immunostimulatory activity with substantial structural and functional equivalence between bell pepper (bp) and carrot (c). The in vitro studies showed that bpRG-I and cRG-I comprise similar immune- and microbiota modulatory potential and the human study demonstrated that bpRG-I was well tolerated and enhanced innate immune responsiveness in vivo. This is an important step towards testing the efficacy of RG-I from bpRG-I or cRG-I in an infection trial in humans.

Our data suggest that in a setting where immunosuppression is reduced, prior analysis of NK cell reactivity cannot identify patients at risk for subsequent graft rejection.

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