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Aims: Agonistic antibodies against neurohumoral receptors can induce cardio‐noxious effects by altering the baseline receptor activity. To estimate the prevalence of autoantibodies directed against the beta‐1 receptor (b1‐AAB) in patients admitted to the hospital for acute heart failure (HF) at (i) baseline and (ii) after 6 months of follow‐up (F6) and (iii) after another 12 months of follow‐up (i.e. 18 months after index hospitalization), to estimate their prognostic impact on clinical outcome (death or first hospitalization for HF). Methods and results: In 47 patients, b1‐AAB were serially determined in serum samples collected at index hospitalization and at 6 months of follow‐up (F6) with a flow cytometry‐based assay: median age 71 years (quartiles 60, 80), 23 (49%) women, 24 (51%) HF with preserved ejection fraction. Beta1‐AAB were detected in three subjects at index hospitalization (6%), and in eight subjects at F6 (17%). There were no differences apparent between patients with and without b1‐AAB at F6 with regard to age, sex, type, duration, or main cause of HF. During the 12 month period following F6 (i.e. up to month 18), eight events occurred. Event‐free survival was associated with prevalence of b1‐AAB at F6. Compared with patients without b1‐AAB at F6, age‐adjusted Cox regression indicated a higher event risk in patients harbouring b1‐AAB, with a hazard ratio of 8.96 (95% confidence interval 1.81–44.50, P = 0.007). Conclusions: Our results suggest a possible adverse prognostic relevance of b1‐AAB in patients with acute HF, but this observation needs to be confirmed in larger patient collectives. [ABSTRACT FROM AUTHOR]

Due to ontogenetic changes in B‐cell developmental lineages, the mature B‐cell compartment constitutes by functionally different B‐cell subsets that emerged from prenatal, early postnatal or adult precursors. While negative selection processes operate primarily within the framework of B‐cell tolerance checkpoints during B‐cell development, further differentiation into distinct B‐cell subsets is additionally induced by positive selection. In addition to endogenous antigens, contact with microbial antigens is also involved in this selection process, with intestinal commensals having a significant influence on the development of a large layer within the B‐cell compartment. The decisive threshold that triggers negative selection seems to be relaxed during fetal B‐cell development, thereby allowing recruitment of polyreactive and also autoreactive B‐cell clones into the mature naïve B‐cell compartment. Almost all of the concepts on B‐cell ontogeny are based on observations in laboratory mice that not only differ from humans in their developmental timeline but also in their composition of commensal microorganisms or rather a lack of exposure to these. In this review, we summarize conceptual findings on B‐cell ontogeny and particularly describe key insights into the developing human B‐cell compartment and immunoglobulin repertoire formation. [ABSTRACT FROM AUTHOR]

Aims: It has been hypothesized that cardiac decompensation accompanying acute heart failure (AHF) episodes generates a pro‐inflammatory environment boosting an adaptive immune response against myocardial antigens, thus contributing to progression of heart failure (HF) and poor prognosis. We assessed the prevalence of anti‐myocardial autoantibodies (AMyA) as biomarkers reflecting adaptive immune responses in patients admitted to the hospital for AHF, followed the change in AMyA titres for 6 months after discharge, and evaluated their prognostic utility. Methods and results: AMyA were determined in n = 47 patients, median age 71 (quartiles 60; 80) years, 23 (49%) female, and 24 (51%) with HF with preserved ejection fraction, from blood collected at baseline (time point of hospitalization) and at 6 month follow‐up (visit F6). Patients were followed for 18 months (visit F18). The prevalence of AMyA increased from baseline (n = 21, 45%) to F6 (n = 36, 77%; P < 0.001). At F6, the prevalence of AMyA was higher in patients with HF with preserved ejection fraction (n = 21, 88%) compared with patients with reduced ejection fraction (n = 14, 61%; P = 0.036). During the subsequent 12 months after F6, that is up to F18, patients with newly developed AMyA at F6 had a higher risk for the combined endpoint of death or rehospitalization for HF (hazard ratio 4.79, 95% confidence interval 1.13–20.21; P = 0.033) compared with patients with persistent or without AMyA at F6. Conclusions: Our results support the hypothesis that AHF may induce patterns of adaptive immune responses. More studies in larger populations and well‐defined patient subgroups are needed to further clarify the role of the adaptive immune system in HF progression. [ABSTRACT FROM AUTHOR]

Superagonistic CD28 stimulation induces IFN- release from mouse T helper 1 cells in vitro and in vivo On a per-cell basis, CD28-SA treatment induced IFN- secretion by OT-II Th1 cells, but not by host-derived CD4 SP + sp and CD8 SP + sp T cells (Fig. Whether isolated CD28 stimulation, as mediated by superagonistic anti-CD28 monoclonal antibodies (CD28-SA), will also trigger IFN- release from mouse Th1 cells is, however, still unknown. Keywords: CD28; Th1 cells; cytokine release; interferon ; Superagonistic antibody EN CD28 Th1 cells cytokine release interferon Superagonistic antibody 738 741 4 03/05/21 20210301 NES 210301 Like human Th1 cells, mouse Th1 cells also secrete IFN- upon stimulation with a superagonistic anti-CD28 monoclonal antibody (CD28-SA). [Extracted from the article]

Importantly, B-cell values in children after resolution of cGvHD were not different from the non-cGvHD control group, which is strikingly different from adult cGvHD-patients, in which B-cell numbers remain depressed at least for two years after alloSCT (Glauzy I et al i , [4]). This indicates that bone marrow B-lymphopoiesis is less affected by cGvHD in children, which is in accordance with observations that children exhibit more bone marrow B-cell precursors after chemotherapy and alloSCT (Bras I et al i , [2]) and more signal joint kappa-deleting recombination excision circles (sjKRECs) (Nakatani I et al i , [8]) in the regenerative phase compared to adults. We extend these findings by showing that the distribution of bone marrow B-cell subsets as well as absolute peripheral B-cell counts exhibit no major alterations neither before nor during cGvHD. In summary, our analysis of T- and B-cell reconstitution reveals a preserved naïve CD4 SP + sp T-cell regeneration and a more robust B-cell regeneration during and after cGvHD in children compared to what is known from adult cGvHD patients. [Extracted from the article]

Donor lymphocyte infusions together with allogeneic hematopoietic stem cell transplantation are routinely used as second‐line treatment for hematological malignancies. Mature T cells in the graft crucially mediate a graft versus leukemia (GvL) response, but also attack healthy tissues in the recipient leading to potentially life‐threatening acute graft versus host disease. Using inducible CD28 knockout C57BL/6 mice as T‐cell donors, we have now assessed whether CD28 costimulation of donor CD4+ and/ or CD8+ T cells is required for an efficient GvL effect after allogeneic T‐cell transplantation into BALB/c recipients. Our results show that CD28 costimulation of donor CD8+ cytotoxic, but not CD4+ helper, T cells was dispensable for curing mice from the BCL‐1 lymphoma. Therefore, donor lymphocyte infusion treated lymphoma‐bearing BALB/c recipient mice showed enhanced long‐term survival when receiving CD28‐deficient as compared to wild‐type donor CD8+ T cells together with wild‐type conventional and regulatory CD4+ T cells. The same was observed when donor CD8+ and conventional and regulatory CD4+ T cells were CD28 deficient. Our data, thus, suggest that systemic CD28 blockade, for example, with the drug FR104 might also reduce acute graft versus host disease in patients after allogeneic hematopoietic stem cell transplantation, while maintaining the protective GvL response. CD28 costimulation of alloreactive CD4+ T cells provides crucial help to CD8+ T cells. Alloreactive CD8+ T cells, however, do not require CD28 costimulation to differentiate into cytotoxic T cells mediating the curative graft versus leukemia (GvL) effect in vivo.. [ABSTRACT FROM AUTHOR]

Introduction For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co-transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)-a potentially life-threatening complication. Methods Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD. Results Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4+ T cell transplantation with the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia-bearing mice after transplantation of allogeneic CD4+ and CD8+ T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4+ T cells with a relative resistance of CD4+ regulatory and CD8+ T cells toward Hsp90 inhibition. Conclusions Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect. [ABSTRACT FROM AUTHOR]

TCRs of invariant NKT (iNKT) cells bind α-galactosylceramide (αGC) loaded CD1d in a highly conserved fashion and show a characteristic TCR gene usage: An 'invariant' α chain with a canonical AV14/ AJ18 rearrangement in mice ( AV24/ AJ18 in humans) is paired with β chains containing characteristic Vβ segments. In the rat, a multimember AV14 gene family increases the variability within this system. This study characterizes CD1d binding of rat AV14 gene segments in TCR transductants as well as CD1d binding and iNKT TCR expression of expanded polyclonal F344 rat iNKT populations. It defines an important role of position 93 at the V-J transition for TCR avidity and species cross-reactivity of the rat iNKT TCR. Furthermore, for the first time we identified variability within the fourth hypervariable loop (HV4) of the α chain as a modulator of CD1d:αGC binding in rat and mouse. Additionally, we confirmed the importance of the CDR2β for CD1d:αGC binding, but also show that the CDR3β may even have opposite effects on binding depending on the pairing α chain. Altogether, we characterized naturally occurring sources of variability for the iNKT TCR and speculate that they rather level than increase the largely germline encoded differences of iNKT TCR ligand avidity. [ABSTRACT FROM AUTHOR]

Upon transplantation of T cells from a CD28 superagonist (CD28-SA) treated donor into an irradiated allogeneic host, the CD28-SA-induced activation and expansion of Treg cells inhibits acute graft versus host disease (aGvHD), while not abrogating the desired graft versus tumor effect. Human peripheral blood CD4+ T cells, however, harbor only very few Treg cells. Therefore, we studied whether polyclonal in vitro prestimulation of conventional, that is Treg-cell-depleted, CD4+ T cells of C57BL/6 mice with CD28-SA-coated paramagnetic beads is sufficient to protect recipient BALB/c mice from aGvHD. CD28-SA prestimulation of conventional CD4+ T cells efficiently protected BALB/c recipient mice from aGvHD and CD28-SA-stimulated CD4+ and CD8+ T cells were capable of mediating long-term protection from the BCL1 lymphoma. The recently completed successful phase I testing of the human CD28-SA TGN1412/TAB08 should greatly facilitate further development of this straightforward method into a novel immunotherapy for patients. [ABSTRACT FROM AUTHOR]

Anergic T cells can survive for long time periods passively in a hyporesponsive state without obvious active functions. Thus, the immunological reason for their maintenance is unclear. Here, we induced peptide-specific anergy in T cells from mice by coculturing these cells with immature murine dendritic cells (DCs). We found that these anergic, nonsuppressive IL-10−Foxp3−CTLA-4+CD25lowEgr2+ T cells could be converted into suppressive IL-10+Foxp3−CTLA-4+CD25highEgr2+ cells resembling type-1 Treg cells (Tr1) when stimulated a second time by immature DCs in vitro. Addition of TGF-β during anergy induction favored Foxp3+ Treg-cell induction, while TGF-β had little effect when added to the second stimulation. Expression of both CD28 and CTLA-4 molecules on anergic T cells was required to allow their conversion into Tr1-like cells. Suppressor activity was enabled via CD28-mediated CD25 upregulation, acting as an IL-2 sink, together with a CTLA-4-mediated inhibition of NFATc1/α activation to shut down IL-2-mediated proliferation. Together, these data provide evidence and mechanistical insights into how persistent anergic T cells may serve as a resting memory pool for Tr1-like cells. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Modulating T cell functions does not alleviate chronic inflammatory skin lesions in K5.TGFβ1 transgenic mice. Experimental Dermatology 2009; 19: 406–415. To use mice with chronic hyperproliferative skin inflammation as psoriasis models, their thorough phenotypic and functional characterization is indispensable. Mice with keratin 5 promoter-controlled overexpression of latent human Transforming Growth Factor (TGF)β1 within the basal epidermis (K5.TGFβ1 mice) show a psoriasiform phenotype, but the underlying pathogenic mechanisms are not entirely clear. To elucidate the contribution of T lymphocytes to the pathogenesis in K5.TGFβ1 mice, we used three complementary approaches: first, peripheral T cells were eradicated via systemic treatment with CD3- or CD4-depleting antibodies. However, this elimination did not alleviate the chronic inflammatory disorder. Second, bone marrow transplantation from transgenic mice into wildtype recipients and vice versa resulted in the expected reconstitution of both adaptive and innate immune system but had little effect on the cutaneous phenotype both in wildtype and transgenic chimeras. Third, based on the hypothesis that the disease course could be modulated by regulatory T cells (Tregs), we expanded Tregs in vivo using a superagonistic anti-CD28 antibody. While this treatment achieved a threefold increase in Foxp3-expressing Tregs, there was little, if any, effect on the chronic skin inflammation. We conclude from our findings that T cells play little, if any, role in the skin lesions of K5.TGFβ1 mice. [ABSTRACT FROM AUTHOR]

T-cell receptor (TCR) stimulation is both central to homeostatic maintenance of CD4+ CD25+ regulatory T cells (Treg cells) in vivo and a prerequisite for the initiation of suppression by Treg cells, both in vivo and in vitro. However, TCR-independent stimulation of Treg cells, e.g. with superagonistic CD28-specific monoclonal antibodies (CD28-SA), not only expands these cells in vivo but, as we show here, also mediates large-scale expansion of rat Treg cells in vitro. Interestingly, CD28-SA stimulation plus interleukin (IL)-2 was even superior to conventional costimulation plus IL-2 in promoting Treg cell growth in vitro. Despite their highly activated phenotype suppression by Treg cells expanded in the absence of TCR stimulation remained fully dependent on TCR-triggering for initiation and cell contact was required to exert suppression. With regard to the regulation of suppression by CD28 stimulation we observed that neither the presence of a conventional anti-CD28 monoclonal antibody nor a CD28-SA generally rendered conventional T cells resistant to suppression by preactivated Treg cells. Taken together, we provide a novel protocol for long-term propagation of Treg cells in vitro and our data are the first to reveal a difference in the signals required for activation and expansion of Treg cells and those, involving the TCR, necessary for the initiation of suppression. [ABSTRACT FROM AUTHOR]