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Alemtuzumab is a monoclonal antibody targeting CD52, used as induction therapy after lung transplantation (LTx). Its engagement produces a long-lasting immunodepletion; however, the mechanisms driving cell reconstitution are poorly defined. We hypothesized that miRNAs are involved in this process. The expression of a set of miRNAs, cytokines and co-signaling molecules was measured with RT-qPCR and flow cytometry in prospectively collected serum samples of LTx recipients, after alemtuzumab or no induction therapy. Twenty-six LTx recipients who received alemtuzumab and twenty-seven matched LTx recipients without induction therapy were included in the analysis. One year after transplantation four miRNAs were differentially regulated: miR-23b (p = 0.05) miR-146 (p = 0.04), miR-155 (p < 0.001) and miR-486 (p < 0.001). Expression of 3 miRNAs changed within the alemtuzumab group: miR-146 (p < 0.001), miR-155 (p < 0.001) and miR-31 (p < 0.001). Levels of IL-13, IL-4, IFN-γ, BAFF, IL-5, IL-9, IL-17F, IL-17A and IL-22 were different one year after transplantation compared to baseline. In no-induction group, concentration of sCD27, sB7.2 and sPD-L1 increased overtime. Expression of miR-23b, miR-146, miR-486, miR-155 and miR-31 was different in LTx recipients who received alemtuzumab compared to recipients without induction therapy. The observed cytokine pattern suggested proliferation of specific B cell subsets in alemtuzumab group and co-stimulation of T-cells in no-induction group. [ABSTRACT FROM AUTHOR]

Summary: Belatacept is a second‐generation cytotoxic T lymphocyte antigen (CTLA)‐4 immunoglobulin (Ig) fusion protein approved for immunosuppression in renal transplant recipients. It was designed intentionally to interrupt co‐stimulation via CD28 by binding to its ligands B7·1 and B7·2. Experimental evidence suggests a potential additional mechanism for CTLA‐4 Ig compounds through binding to B7 molecules expressed on antigen‐presenting cells (APCs) and up‐regulation of indoleamine 2,3‐dioxygenase (IDO), an immunomodulating enzyme that catalyzes the degradation of tryptophan to kynurenine and that down‐regulates T cell immunity. So far it remains unknown whether belatacept up‐regulates IDO in transplant recipients. We therefore investigated whether belatacept therapy enhances IDO activity in liver transplant recipients enrolled in a multi‐centre, investigator‐initiated substudy of the Phase II trial of belatacept in liver transplantation (IM103‐045). Tryptophan and kynurenine serum levels were measured during the first 6 weeks post‐transplant in liver transplant patients randomized to receive either belatacept or tacrolimus‐based immunosuppression. There was no significant difference in IDO activity, as indicated by the kynurenine/tryptophan ratio, between belatacept and tacrolimus‐treated patients in per‐protocol and in intent‐to‐treat analyses. Moreover, no evidence was found that belatacept affects IDO in human dendritic cells (DC) in vitro. These data provide evidence that belatacept is not associated with detectable IDO induction in the clinical transplant setting compared to tacrolimus‐treated patients. [ABSTRACT FROM AUTHOR]

Organ transplantation is the treatment of choice for patients with end-stage organ failure, but chronic immunosuppression is taking its toll in terms of morbidity and poor efficacy in preventing late graft loss. Therefore, a drug-free state would be desirable where the recipient permanently accepts a donor organ while remaining otherwise fully immunologically competent. Mouse studies unveiled mixed chimerism as an effective approach to induce such donor-specific tolerance deliberately and laid the foundation for a series of clinical pilot trials. Nevertheless, its widespread clinical implementation is currently prevented by cytotoxic conditioning and limited efficacy. Therefore, the use of mouse studies remains an indispensable tool for the development of novel concepts with potential for translation and for the delineation of underlying tolerance mechanisms. Recent innovations developed in mice include the use of pro-apoptotic drugs or regulatory T cell (Treg) transfer for promoting bone marrow engraftment in the absence of myelosuppression and new insight gained in the role of innate immunity and the interplay between deletion and regulation in maintaining tolerance in chimeras. Here, we review these and other recent advances in murine studies inducing transplantation tolerance through mixed chimerism and discuss both the advances and roadblocks of this approach. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 Phl p 5 into myeloablated recipients led to high levels of chimerism (i.e. macrochimerism) and completely abrogated Phl p 5-specific immunity despite repeated immunizations with Phl 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 Phl 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 Phl p 5 and Bet 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 Phl 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 Phl 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. [ABSTRACT FROM AUTHOR]

Patients with "hepatic" bone disease exhibit increased fracture incidence. The effects on bone material properties, their changes due to orthotopic liver transplantation (OLT), as well as zolendronate (ZOL) treatment have not yet been investigated. We studied bone mineralization density distribution (BMDD) in paired transiliacal biopsies (at and 6 months after OLT) from patients (control CON n = 18, treatment group ZOL n = 21, the latter treated with i.v. ZOL at doses of 4 mg/month) for how bone at the material level was affected by the "hepatic" disease in general, as well as by OLT and ZOL in particular. (1) BMDD parameters at baseline reflected disturbed bone matrix mineralization in "hepatic" bone disease combined with low turnover. Trabecular bone displayed a decrease in mean and most frequent calcium concentration (Ca(MEAN) -2.9% and Ca(PEAK) -2.8%, respectively; both P < 0.001), increased heterogeneity of mineralization (Ca(WIDTH) +12.2%, P = 0.01), and increased percentage of bone areas with low mineralization (Ca(LOW) +32.4%, P = 0.02) compared to normal; however, there were no differences compared to cortical bone. (2) Six months after OLT, ZOL-treated trabecular bone displayed reduced Ca(LOW) (-32.0%, P = 0.047), cortical bone increased Ca(MEAN) (+4.2%, P = 0.009), increased Ca(PEAK) (+3.3%, P = 0.040), and decreased Ca(LOW) (-55.7, P = 0.038) compared to CON and increased Ca(MEAN) compared to baseline (+1.9, P = 0.032) without any signs of hyper- or defective mineralization. These changes as consequence of the antiresorptive action of ZOL visible already after 6 months result in beneficial effects on bone matrix mineralization, likely contributing to the significant decrease in fracture incidence observed in these patients 2 years post transplantation. [ABSTRACT FROM AUTHOR]

Background: In January 1999 a new kidney allocation program was launched by the Eurotransplant Foundation, the ‘Eurotransplant Senior Program’ (ESP). Cadaveric donors above the age of 65 yr are allocated to kidney transplant recipients of the same age group. Methods: Using a single-center database, 91 patients who underwent first renal transplantation at the age of 65 yr and older in the years 1999–2002 were identified. Fifty-six patients were transplanted through ESP allocation (study group) and 35 patients (control group) via normal Eurotransplant Kidney Allocation System (ETKAS) procedure. Results: Age, sex and comorbid conditions did not differ by group. The rate of acute rejection episodes, primary non-function, delayed graft function, perioperative mortality did not differ by group. Serum creatinine was significantly lower in the ETKAS group (1.3 vs. 1.9 mg/dL; p = 0.015) from six months after the transplantation on. Overall graft survival at six yr was 56% in the ETKAS group and 52% in the ESP group. With 73% in the ETKAS group and 71% in the ESP group, cumulative patient survival according to the Kaplan–Meier estimation was not statistically different at five yr. Conclusions: We did not find a relevant difference in the outcome between young and old kidney transplants in old recipients after this long observation period. [ABSTRACT FROM AUTHOR]