BACKGROUND:IgE-mediated allergy is a common disease characterized by a harmful immune response towards otherwise harmless environmental antigens. Induction of specific immunological non-responsiveness towards allergens would be a desirable goal. Blockade of costimulatory pathways is a promising strategy to modulate the immune response in an antigen-specific manner. Recently, OX40 (CD134) was identified as a costimulatory receptor important in Th2-mediated immune responses. Moreover, synergy between OX40 blockade and 'conventional' costimulation blockade (anti-CD40L, CTLA4Ig) was observed in models of alloimmunity. OBJECTIVE:We investigated the potential of interfering with OX40 alone or in combination with CD40/CD28 signals to influence the allergic immune response. METHODS:The OX40 pathway was investigated in an established murine model of IgE-mediated allergy where BALB/c mice are repeatedly immunized with the clinically relevant grass pollen allergen Phl p 5. Groups were treated with combinations of anti-OX40L, CTLA4Ig and anti-CD40L. In selected mice, Tregs were depleted with anti-CD25. RESULTS:Blockade of OX40L alone at the time of first or second immunization did not modulate the allergic response on the humoral or effector cell levels but slightly on T cell responses. Administration of a combination of anti-CD40L/CTLA4Ig delayed the allergic immune response, but antibody production could not be inhibited after repeated immunization even though the allergen-specific T cell response was suppressed in the long run. Notably, additional blockade of OX40L had no detectable supplementary effect. Immunomodulation partly involved regulatory T cells as depletion of CD25(+) cells led to restored T cell proliferation. CONCLUSIONS AND CLINICAL RELEVANCE:Collectively, our data provide evidence that the allergic immune response towards Phl p 5 is independent of OX40L, although reduction on T cell responses and slightly on the asthmatic phenotype was detectable. Besides, no relevant synergistic effect of OX40L blockade in addition to CD40L/CD28 blockade could be detected. Thus, the therapeutic potential of OX40L blockade for IgE-mediated allergy appears to be ineffective in this setting.

The mixed chimerism approach achieves donor-specific tolerance in organ transplantation, but clinical use is inhibited by the toxicities of current bone marrow (BM) transplantation (BMT) protocols. Blocking the CD40:CD154 pathway with anti-CD154 monoclonal antibodies (mAbs) is exceptionally potent in inducing mixed chimerism, but these mAbs are clinically not available. Defining the roles of donor and recipient CD40 in a murine allogeneic BMT model, we show that CD4 or CD8 activation through an intact direct or CD4 T cell activation through the indirect pathway is sufficient to trigger BM rejection despite CTLA4Ig treatment. In the absence of CD4 T cells, CD8 T cell activation via the direct pathway, in contrast, leads to a state of split tolerance. Interruption of the CD40 signals in both the direct and indirect pathway of allorecognition or lack of recipient CD154 is required for the induction of chimerism and tolerance. We developed a novel BMT protocol that induces mixed chimerism and donor-specific tolerance to fully mismatched cardiac allografts relying on CD28 costimulation blockade and mTOR inhibition without targeting the CD40 pathway. Notably, MHC-mismatched/minor antigen-matched skin grafts survive indefinitely whereas fully mismatched grafts are rejected, suggesting that non-MHC antigens cause graft rejection and split tolerance.

Bone marrow (BM) transplantation under costimulation blockade induces chimerism and tolerance. Cotransplantation of donor T cells (contained in substantial numbers in mobilized peripheral blood stem cells and donor lymphocyte infusions) together with donor BM paradoxically triggers rejection of donor BM through undefined mechanisms. Here, nonmyeloablatively irradiated C57BL/6 recipients simultaneously received donor BM (BALB/c) and donor T cells under costimulation blockade (anti-CD154 and CTLA4Ig). Donor CD4, but not CD8 cells, triggered natural killer-independent donor BM rejection which was associated with increased production of IL-6, interferon gamma (IFN-γ) and IL-17A. BM rejection was prevented through neutralization of IL-6, but not of IFN-γ or IL-17A. IL-6 counteracted the antiproliferative effect of anti-CD154 in vitro. Rapamycin and anti-lymphocyte function-associated antigen 1 negated this effect of IL-6 in vitro and prevented BM rejection in vivo. Simultaneous cotransplantation of (BALB/cxB6)F1, recipient or irradiated donor CD4 cells, or late transfer of donor CD4 cells did not lead to BM rejection, whereas cotransplantation of third party CD4 cells did. Transferred donor CD4 cells became activated, rapidly underwent apoptosis and triggered activation and proliferation of recipient T cells. Collectively, these results provide evidence that donor T cells recognizing the recipient as allogeneic lead to the release of IL-6, which abolishes the effect of anti-CD154, triggering donor BM rejection through bystander activation.

Specific immunotherapy is the only curative treatment currently available for IgE-mediated allergy and preventive strategies are lacking altogether. We have recently reported that molecular chimerism induces durable tolerance in experimental models of allergy, thus potentially providing a new approach for the treatment and prevention of allergic diseases. Molecular chimerism is a gene-therapy approach for tolerance induction toward defined disease-causing antigens. In proof-of-concept studies, we introduced a clinically relevant grass pollen allergen into hematopoietic stem cells and transplanted those modified cells into preconditioned syngeneic mice. Long-lasting and robust tolerance toward the allergen was achieved. In our most recent studies published in Clinical and Experimental Allergy we demonstrated that milder, non-myeloablative conditioning is sufficient to induce tolerance. Our results revealed that, in contrast to other rodent models of chimerism, persistent microchimerism suffices to induce lasting tolerance at the T cell, B cell and effector cell levels in IgE-mediated allergy. This article addendum provides a summary of the recent paper and its implications.

Summary Background Development of antigen‐specific preventive strategies is a challenging goal in IgE ‐mediated allergy. We have recently shown in proof‐of‐concept experiments that allergy can be successfully prevented by induction of durable tolerance via molecular chimerism. Transplantation of syngeneic hematopoietic stem cells genetically modified to express the clinically relevant grass pollen allergen P hl p 5 into myeloablated recipients led to high levels of chimerism (i.e. macrochimerism) and completely abrogated P hl p 5‐specific immunity despite repeated immunizations with P hl p 5. Objective It was unclear, however, whether microchimerism (drastically lower levels of chimerism) would be sufficient as well which would allow development of minimally toxic tolerance protocols. Methods Bone marrow cells were transduced with recombinant viruses integrating P hl p 5 to be expressed in a membrane‐anchored fashion. The syngeneic modified cells were transplanted into non‐myeloablated recipients that were subsequently immunized repeatedly with P hl p 5 and B et v 1 (control). Molecular chimerism was monitored using flow cytometry and PCR . T cell, B ‐cell and effector‐cell tolerance were assessed by allergen‐specific proliferation assays, isotype levels in sera and RBL assays. Results Here we demonstrate that transplantation of P hl p 5‐expressing bone marrow cells into recipients having received non‐myeloablative irradiation resulted in chimerism persisting for the length of follow‐up. Chimerism levels, however, declined from transient macrochimerism levels to persistent levels of microchimerism (followed for 11 months). Notably, these chimerism levels were sufficient to induce B ‐cell tolerance as no P hl p 5‐specific IgE and other high affinity isotypes were detectable in sera of chimeric mice. Furthermore, T ‐cell and effector‐cell tolerance were achieved. Conclusions and Clinical Relevance Low levels of persistent molecular chimerism are sufficient to induce long‐term tolerance in IgE ‐mediated allergy. These results suggest that it will be possible to develop minimally toxic conditioning regimens sufficient for low level engraftment of genetically modified bone marrow.

Background: Mixed chimerism is an effective strategy for the induction of transplantation tolerance but widespread clinical application is impeded by the toxicities of current bone marrow (BM) transplantation (BMT) protocols. We combined the therapeutic use of regulatory T cells (Tregs) with the mixed chimerism approach to achieve a protocol that is both effective and safe. Previous data demonstrate that Treg therapy allows engraftment of conventional doses of fully mismatched BM without the need for irradiation, leading to robust skin and humoral tolerance, preventing acute and chronic rejection. Here we investigated regulatory mechanisms and specificity of Tregs in this novel Treg-chimerism protocol. Methods: B6 recipients received 20×106 fully mismatched Balb/c BM cells, under costimulation blockade and short-course rapamycin together with 0.5-4×106 polyclonal WT Tregs from either recipient, donor or third-party strains. Multilineage chimerism was followed by flow-cytometric analysis, tolerance was assessed by heart and skingrafts and analysis of anti-donor Abs. Persistence of Tregs was assessed by PCR in lymphoid organs. Regulatory mechanisms were investigated by analysis of donor-reactive T cells and MLRs. Results: Therapeutic application of as few as 0.5×106 (25x106/kg) polyclonal recipient Tregs reliably induces mixed chimerism and tolerance in a non-cytotoxic BMT model. MLR data and analysis of donor-reactive T cells revealed donor-specific tolerance in the absence of peripheral deletion early after BMT, which was also confirmed by early skingrafts. Treg treated chimeras lack anti-donor antibodies and absence of chronic rejection was confirmed by histologic analysis of heart allografts. Donor heats remained functional for the follow up of >100d. Pathohistologic examination showed no signs of cardiac allograft vasculopathy. Hearts were devoid of interstitial fibrosis, vasculitis and myointimal thickening. Donor-specific tolerance was robust and sustained despite repeated challenge with secondary donor and third-party grafts. PCR analysis revealed preserved homing abilities and limited life-span of transferred Tregs. Tregs home to lymph nodes and spleen, but not to thymus or BM early after transplantation (7 days), no transferred Tregs could be detected in lymphoid organs or skingrafts late after BMT (30 weeks). Tregs derived from donor or third-party strains led to transient chimerism in some mice, however, longterm donor-specific tolerance could not be achieved. Conclusions: Therapeutic Treg treatment promotes engraftment of allogeneic BM and reliably induces mixed chimerism with clinical relevant Treg numbers. Although central tolerance is established, peripheral deletion progresses only slowly. Regulatory mechanisms are sufficient to maintain donor-specific tolerance before peripheral deletion takes place and seem to be more important than in BMT protocols relying on myelosuppression. Transferred Tregs are suggested to be short-lived, suggesting an infectious-like tolerance mechanism in Treg treated chimeras. Recipient derived Tregs seem to be superior over donor or third-party Tregs in the promotion of BM engraftment. Due to positive selection for recipient MHC, recipient Tregs might be superior over donor and third-party Tregs in being activated by the indirect pathway of antigen presentation.

Alte, auch desorientierte Menschen haben eine intuitive Weisheit. Sie zu verstehen, gilt es zu lernen. Hinter der Desorientierung eines Menschen liegt Wissen, das ein ganzes Menschenleben lang aufgebaut und nur scheinbar nicht abgerufen werden kann. Wenn das Augenlicht altersbedingt nachlässt, das Gehör immer weniger Umwelt vermittelt, dann bleibt die innere Welt übrig. Kommunikation beinhaltet nicht nur Wörter, sondern ebenso "paralinguistische Phänomene" (Watzlawick) wie Schnelligkeit oder Langsamkeit der Sprache, den Tonfall, Pausen, Lachen, Seufzen, Körperhaltung und Ausdrucksbewegungen. Desorientierung schränkt menschliche Ausdrucksfähigkeit ein. Kommunikation mit einem desorientierten Menschen beinhaltet die Frage des Wie - Wie erreiche ich ihn, verstehe ich, was er mir sagen möchte, kann ich ihm antworten?

Herausragende wissenschaftliche, publizistische oder individuelle Leistungen werden mit dem Alois-Alzheimerpreis gewürdigt. Die Preisträgerin 2009 ist Naomi Feil. Die feierliche Ehrung mit einer Laudatio von Maria Hoppe, Gründungsmitglied des Österreichschen Instituts für Validation, fand Ende November im Wiener Rathaus statt.

Ramsey, H.1; Klaus, C.2; Pilat, N.3; Gattringer, M.2; Baranyi, U.2; Hock, K.2; Muehlbacher, F.2; Wekerle, T.3 Author Information

In Pflege und Betreuung stehen die Qualität tragfähiger Beziehungen, pflegerisches Engagement, professionelle Fürsorge und sinnvolle Alltagsgestaltung im Vordergrund des Pflegeprozesses. Die österreichische Theoretikerin Irmgard Kappelmüller definiert den Pflegeprozess als erwartetes Ergebnis: „Der Patient und andere Personen sollen in die Zielerstellung einbezogen werden. Gemeinsam erstellte Ziele sind oft realistischer, die Chance, dass sie erreicht werden, ist größer.“ Was heißt das bei desorientierten, demenzkranken Menschen? Wie schafft man es, dass Bewohner sich wie zu Hause fühlen?

Jede Beziehungspflege ist der Versuch die Bedingungen der Selbstorganisation von Menschen zu optimieren. Das gilt für alle pflegebedürftigen Menschen, in allen Lebensaltern. Sie hängt an zwei Sichtweisen: Wie sieht ein professionell Pflegender den zu Pflegenden und wie sehen pflegebedürftige Menschen sich selbst. Ohne Dialog, Kompetenz und Reflexion sind tragfähige Pflegebeziehungen kaum möglich. Deswegen müssen in Pflege und Betreuung die Qualität tragfähiger Beziehungen, pflegerisches Engagement, professionelle Fürsorge, sinnvolle Alltagsgestaltung im Vordergrund stehen.

Schwaiger, E; Christoph, K; Baranyi, U; Pilat, N; Korom, S; Matheeussen, V; De Meester, I; Mühlbacher, F; Wekerle, T Author Information

Klaus, C; Pilat, N; Schwaiger, E; Gattringer, M; Muehlbacher, F; Wekerle, T Author Information