No augmentation of indoleamine 2,3-dioxygenase (IDO) activity through belatacept treatment in liver transplant recipients.

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.

Minor Antigen Disparities Impede Induction of Long Lasting Chimerism and Tolerance through Bone Marrow Transplantation with Costimulation Blockade.

Mixed chimerism and tolerance can be successfully induced in rodents through allogeneic bone marrow transplantation (BMT) with costimulation blockade (CB), but varying success rates have been reported with distinct models and protocols. We therefore investigated the impact of minor antigen disparities on the induction of mixed chimerism and tolerance. C57BL/6 (H2) mice received nonmyeloablative total body irradiation (3 Gy), costimulation blockade (anti-CD40L mAb and CTLA4Ig), and 2 × 10 bone marrow cells (BMC) from either of three donor strains: Balb/c (H2) (MHC plus multiple minor histocompatibility antigen (mHAg) mismatched), B10.

The role of natural killer T cells in costimulation blockade-based mixed chimerism.

Distinct lymphocyte populations have been identified that either promote or impede the establishment of chimerism and tolerance through allogeneic bone marrow transplantation (BMT). Natural killer T (NKT) cells have pleiotropic regulatory properties capable of either augmenting or downmodulating various immune responses. We investigated in this study whether NKT cells affect outcome in mixed chimerism models employing fully mismatched nonmyeloablative BMT with costimulation blockade (CB).

Anti-CD154 mAb and rapamycin induce T regulatory cell mediated tolerance in rat-to-mouse islet transplantation.

Background: Anti-CD154 (MR1) monoclonal antibody (mAb) and rapamycin (RAPA) treatment both improve survival of rat-to-mouse islet xenograft. The present study investigated the effect of combined RAPA/MR1 treatment on rat-to-mouse islet xenograft survival and analyzed the role of CD4(+)CD25(+)Foxp3(+) T regulatory cells (Treg) in the induction and maintenance of the ensuing tolerance.

Methodology/principal Findings: C57BL/6 mice were treated with MR1/RAPA and received additional monoclonal anti-IL2 mAb or anti CD25 mAb either early (0-28 d) or late (100-128 d) post-transplantation.

Adjuvant bisphosphonates in endocrine-responsive breast cancer: what is their place in therapy?

Recent advances in the treatment of early breast cancer have improved clinical outcomes and prolonged survival, especially in women with endocrine-responsive disease. However, cancer therapies including cytotoxic chemotherapy, ovarian suppression, and aromatase inhibitors can drastically reduce circulating estrogen, increasing bone loss and fracture risk. Because most women with early breast cancer will live for many years, it is important to protect bone health during cancer therapy.

Toward MSC in solid organ transplantation: 2008 position paper of the MISOT study group.

The following position paper summarizes the recommendations for early clinical trials and ongoing basic research in the field of mesenchymal stem cell-induced solid organ graft acceptance--agreed upon on the first meeting of the Mesenchymal Stem Cells In Solid Organ Transplantation (MISOT) study group in late 2008.

Is Endocrine Therapy Really Pleasant? Considerations about the Long-Term Use of Antihormonal Therapy and Its Benefit/Side Effect Ratio.

Endocrine therapy has become a key part in the adjuvant treatment of hormone responsive breast cancer. The positive effect on relapse risk reduction is well defined, but therapy is not free from bothersome side effects for which estrogen deprivation accounts to a great extent. Since endocrine therapy is usually prescribed for 5 years or longer to optimally display its protective effect, and because physical strain is missing, good tolerability and safety properties are important, particularly in low-risk patients.

Murine mobilized peripheral blood stem cells have a lower capacity than bone marrow to induce mixed chimerism and tolerance.

Allogeneic bone marrow transplantation (BMT) under costimulation blockade allows induction of mixed chimerism and tolerance without global T-cell depletion (TCD). The mildest such protocols without recipient cytoreduction, however, require clinically impracticable bone marrow (BM) doses. The successful use of mobilized peripheral blood stem cells (PBSC) instead of BM in such regimens would provide a substantial advance, allowing transplantation of higher doses of hematopoietic donor cells.

CTLA4Ig promotes the induction of hematopoietic chimerism and tolerance independently of Indoleamine-2,3-dioxygenase.

Bone marrow transplantation (BMT) under costimulation blockade induces mixed chimerism and tolerance in rodent models. Recent data, predominantly from in vitro studies, suggest that in addition to blocking the CD28 costimulation pathway CTLA4Ig also acts through upregulating the tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO). Here we demonstrate that even though CTLA4Ig is critically required for the induction of chimerism and tolerance in a murine model of nonmyeloablative BMT, IDO activity is not.

Costimulation blockade inhibits allergic sensitization but does not affect established allergy in a murine model of grass pollen allergy.

Type I allergy is characterized by the development of an initial Th2-dependent allergen-specific IgE response, which is boosted upon a subsequent allergen encounter. Although the immediate symptoms of allergy are mainly IgE-mediated, allergen-specific T cell responses contribute to the late phase as well as to the chronic manifestations of allergy. This study investigates the potential of costimulation blockade with CTLA4Ig and an anti-CD154 mAb for modifying the allergic immune response to the major timothy grass pollen allergen Phl p 5 in a mouse model.

Induction of mixed chimerism through transplantation of CD45-congenic mobilized peripheral blood stem cells after nonmyeloablative irradiation.

Clinical translation of the mixed-chimerism approach for inducing transplantation tolerance would be facilitated if mobilized peripheral blood stem cells (mPBSCs) could be used instead of bone marrow cells (BMCs). Because the use of mPBSCs for this purpose has not been investigated in nonmyeloablative murine protocols, we explored the engraftment potential of mPBSCs in a CD45-congenic model as a first step. After 2, 1.

Short-term immunosuppression facilitates induction of mixed chimerism and tolerance after bone marrow transplantation without cytoreductive conditioning.

Background: Induction of mixed chimerism and tolerance usually requires cytoreduction or transplantation of high numbers of bone marrow cells (BMC). However, such protocols have only a suboptimal success rate and, more importantly, equivalent numbers of BMC cannot be routinely obtained in the clinical setting. The authors therefore evaluated whether a short-course of immunosuppression (IS) given in addition to co-stimulation blockade would facilitate chimerism induction and allow reduction of the minimally required number of BMC without cytoreduction.

The role of non-deletional tolerance mechanisms in a murine model of mixed chimerism with costimulation blockade.

Peripheral and central clonal deletion are important tolerance mechanisms in models using bone marrow transplantation (BMT) with costimulation blockade (CB). However, since tolerance can be found before peripheral deletion is complete and since elimination of recipient CD4(+) cells at the time of BMT prevents tolerance induction, we investigated the potential roles of regulation and anergy in such a murine model. We found that transient elimination of CD25(+) cells or neutralization of IL2 immediately after BMT and CB prevented the induction of skin graft tolerance.

Mechanisms of tolerance induction through the transplantation of donor hematopoietic stem cells: central versus peripheral tolerance.

The transplantation of donor hematopoietic stem cells has been used successfully in numerous experimental settings to induce donor-specific tolerance. After appropriate host conditioning, hematopoietic stem-cell transplantation leads to a lasting state of donor macrochimerism that is associated with a robust form of tolerance. One of the key factors in the success of this approach is its reliance on intrathymic clonal deletion to ensure lifelong tolerization of newly developing T cells.

The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade.

We recently developed a murine protocol for the induction of allogeneic mixed chimerism and tolerance employing nonmyeloablative total body irradiation (TBI), standard-dose bone marrow transplantation (BMT), and costimulation blockade (cobl) with an anti-CD154 monoclonal antibody (mAb) plus CTLA4Ig. We now evaluated whether a short course (1 month) of immunosuppressive drugs, which would be ethically required in the clinical setting of organ transplantation to prevent graft loss in case tolerance is not achieved, interferes with tolerance induced with this regimen. Our results show that calcineurin inhibitors (cyclosporin A [CyA] or tacrolimus [FK]) inhibit development of long-term chimerism and abrogate tolerance induction in this model.

Mechanisms of transplant tolerance induction using costimulatory blockade.

The potential use of costimulation-blocking reagents to induce transplantation tolerance has recently created considerable excitement. Recent evidence has begun to delineate the mechanisms by which these powerful effects occur. It has become increasingly clear, firstly, that T cell costimulation is mediated by a delicate network of signaling pathways and, secondly, that interference with these systems can lead to numerous different tolerance mechanisms, including immune regulation, anergy and deletion.