Clinical transplantation tolerance: a myth no more, but..

More than 55 years after the description of the phenomenon of acquired immunologic tolerance to transplant antigens by Medawar and colleagues, the holy grail of transplantation is a myth no more. Establishment of the Immune Tolerance Network in 1999 changed the approach used to achieve clinical tolerance by translating advances in the field of immunology in general and in tolerance in particular from experimental animal strategies into human clinical trials, and initial results have been promising. Despite these advances, scientific and operational challenges still face the transplantation community and affect progress.

Regulatory T cells in transplantation: what we know and what we do not know.

Current immunosuppressive regimens suppress alloimmunity by nonspecifically targeting T-cell proliferation, differentiation, and activation. In doing so, they have been effective in dramatically reducing rates of acute rejection and improving short-term allograft survival. However, this is often at the expense of overimmunosuppression.

Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells.

The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance. Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by IL-17-producing CD8 T (T17) cells.

Blockade of peroxynitrite-induced neural stem cell death in the acutely injured spinal cord by drug-releasing polymer.

Therapeutic impact of neural stem cells (NSCs) for acute spinal cord injury (SCI) has been limited by the rapid loss of donor cells. Neuroinflammation is likely the cause. As there are close temporal-spatial correlations between the inducible nitric oxide (NO) synthase expression and the donor NSC death after neurotrauma, we reasoned that NO-associated radical species might be the inflammatory effectors which eliminate NSC grafts and kill host neurons.

Gene therapy in type 1 diabetes.

Type 1 diabetes (T1D) is caused by the autoimmune-mediated destruction of insulin-producing beta cells in the pancreas. T1D affects as many as 3 million patients in the United States alone, with 15,000 new cases developing every year (Juvenile Diabetes Research Foundation), and presently there is no cure for T1D. In recent years, there has been a great deal of interest in developing gene therapy approaches to treat T1D.

Neuropathology of central nervous system arterial syndromes. Part I: the supratentorial circulation.

The objective of this review is to illustrate the principal cerebrovascular arterial pathoanatomical syndromes using the unique collection of whole brain sections in the Raymond Escourolle Neuropathology Laboratory at Salpêtrière in Paris. The arterial supratentorial syndromes are presented in Part I; the infratentorial and spinal cord syndromes will be presented subsequently in Part II. No attempt is made to be all-inclusive in the review of the literature; rather, we cite only those bibliographic references that are historically noteworthy and with some exceptions that particularly emphasize the neuropathologic rather than radiographic/imaging aspects of the vascular syndromes.

A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy.

T-bet plays a crucial role in Th1 development. We investigated the role of T-bet in the development of allograft rejection in an established MHC class II-mismatched (bm12 into B6) model of chronic allograft vasculopathy (CAV). Intriguingly, and in contrast to IFN-gamma(-/-) mice that are protected from CAV, T-bet(-/-) recipients develop markedly accelerated allograft rejection accompanied by early severe vascular inflammation and vasculopathy, and infiltration by predominantly IL-17-producing CD4 T cells.

Prevention of type 1 diabetes in NOD mice by genetic engineering of hematopoietic stem cells.

Type 1 diabetes is caused by autoimmune destruction of insulin-producing cells in the pancreas. Type 1 diabetes could potentially be treated by islet transplantation; however, the recurrence of autoimmunity leads to the destruction of islet grafts in a relatively short time frame. Therefore, a major goal of diabetes research is the induction of tolerance in diabetic patients to prevent recurrence of diabetes.

Induction of transplantation tolerance by combining non-myeloablative conditioning with delivery of alloantigen by T cells.

The observation that bone marrow derived hematopoietic cells are potent inducers of tolerance has generated interest in trying to establish transplantation tolerance by inducing a state of hematopoietic chimerism through allogeneic bone marrow transplantation. However, this approach is associated with serious complications that limit its utility for tolerance induction. Here we describe the development of a novel approach that allows for tolerance induction without the need for an allogeneic bone marrow transplant by combining non-myeloablative host conditioning with delivery of donor alloantigen by adoptively transferred T cells.

Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice.

Islet allografts are subject to alloimmune and autoimmune destruction when transplanted into autoimmune prone animals or humans. The ICOS-B7h pathway plays a role in alloimmune responses, but its function in autoimmunity against islet cells is controversial. We investigated the role of ICOS signaling in autoimmune and alloimmune responses in NOD mice.

New approaches to the prevention of organ allograft rejection and tolerance induction.

The therapeutic use of organ allograft transplantation is dependent on the discovery and clinical application of immunologic strategies to blunt the immune response and prevent graft rejection. It was the discovery of powerful immunotherapeutics such as cyclosporine A and rapamycin that has allowed for the widespread use of organ transplantation to treat organ failure. However, despite the attainment of impressive survival rates 1 year after organ transplantation, a significant number of organ allografts are lost to immune-mediated chronic rejection.

Mechanisms of PDL1-mediated regulation of autoimmune diabetes.

The PD-1-PDL1 pathway plays a critical role in regulating autoimmune diabetes as blockade or deficiency of PD-1 or PDL1 results in accelerated disease in NOD mice. We explored the cellular mechanisms involved in the regulation of these autoimmune responses by investigations involving various gene-deficient mice on the NOD background. Administration of blocking anti-PDL1 antibody to CD4+ T cell-deficient, CD8+ T cell-deficient and B cell-deficient mice demonstrated that PDL1-mediated regulation of autoreactive CD4+ and CD8+ T cells is critical for diabetes development.

Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function.

It has been suggested that T cell immunoglobulin mucin (Tim)-1 expressed on T cells serves to positively costimulate T cell responses. However, crosslinking of Tim-1 by its ligand Tim-4 resulted in either activation or inhibition of T cell responses, thus raising the issue of whether Tim-1 can have a dual function as a costimulator. To resolve this issue, we tested a series of monoclonal antibodies specific for Tim-1 and identified two antibodies that showed opposite functional effects.

Transplant tolerance through costimulation blockade--are we there yet?

Achieving a tolerant state specific to the transplanted graft without subjecting patients to the risks of non-specific immunosuppression is the goal of transplant immunologists. In spite of the success achieved with currently available immunosuppresive therapies over acute rejection, an ongoing T cell mediated alloimmune response still poses a major challenge to the health of an allograft through chronic rejection. Modulating these destructive alloresponses through T cell costimulation blockade is a promising area of interest.

Physical activity-mediated functional recovery after spinal cord injury: potential roles of neural stem cells.

As data elucidating the complexity of spinal cord injury pathophysiology emerge, it is increasingly being recognized that successful repair will probably require a multifaceted approach that combines tactics from various biomedical disciplines, including pharmacology, cell transplantation, gene therapy and material sciences. Recently, new evidence highlighting the benefit of physical activity and rehabilitation interventions during the post-injury phase has provided novel possibilities in realizing effective repair after spinal cord injury. However, before a comprehensive therapeutic strategy that optimally utilizes the benefits of each of these disciplines can be designed, the basic mechanisms by which these various interventions act must be thoroughly explored and important synergistic and antagonistic interactions identified.

Regulation of oxidative stress responses by ataxia-telangiectasia mutated is required for T cell proliferation.

Mutations in the gene encoding ataxia-telangiectasia (A-T) mutated (Atm) cause the disease A-T, characterized by immunodeficiency, the molecular basis of which is not known. Following stimulation through the TCR, Atm-deficient T cells and normal T cells in which Atm is inhibited undergo apoptosis rather than proliferation. Apoptosis is prevented by scavenging reactive oxygen species (ROS) during activation.

Maternal acceptance of the fetus: true human tolerance.

Induction and maintenance of immunologic tolerance in humans remains a desirable but elusive goal. Therefore, understanding the physiologic mechanisms of regulation of immune responses is highly clinically relevant for immune-mediated diseases (e.g.

T cell costimulatory pathways in allograft rejection and tolerance: what's new?

Purpose Of Review: The induction or maintenance of allograft tolerance remains an ongoing challenge. One approach to the development of tolerogenic strategies involves targeting T-cell costimulatory signals. The two most widely studied costimulatory pathways are the CD28/B7 and CD40/CD154 pathways, and blocking of both, either alone or in combination, has been shown to prolong allograft survival in rodents and primates.