Explore the vast range of titles available.

The definition of immune tolerance to allogeneic tissue and organ transplants in laboratory animals and humans continues to be the acceptance of the donor graft, rejection of third-party grafts, and specific unresponsiveness of recipient immune cells to the donor alloantigens in the absence of immunosuppressive treatments. Actively acquired tolerance was achieved in mice more than 60 years ago by the establishment of mixed chimerism in neonatal mice. Once established, mixed chimerism was self-perpetuating and allowed for acceptance of tissue transplants in adults. Successful establishment of tolerance in humans has now been reported in several clinical trials based on the development of chimerism after combined transplantation of hematopoietic cells and an organ from the same donor. This review examines the mechanisms of organ graft acceptance after establishment of mixed chimerism (allo-tolerance) or complete chimerism (self-tolerance), and compares the development of graft versus host disease (GVHD) and graft versus tumor (GVT) activity in complete and mixed chimerism. GVHD, GVT activity, and complete chimerism are also discussed in the context of bone marrow transplantation to treat hematologic malignancies. The roles of transient versus persistent mixed chimerism in the induction and maintenance of tolerance and organ graft acceptance in animal models and clinical studies are compared. Key differences in the stability of mixed chimeras and tolerance induction in MHC matched and mismatched rodents, large laboratory animals, and humans are examined to provide insights into the safety and efficacy of translation of results of animal models to clinical trials.

A patient received a kidney graft from his HLA-identical brother, followed by an infusion of CD34+ hematopoietic stem cells from the same donor. An apparent state of immunologic tolerance to the kidney allograft developed, allowing withdrawal of all immunosuppressive therapy within 6 months. A patient received a kidney graft from his HLA-identical brother, followed by an infusion of CD34+ hematopoietic stem cells from the same donor. Immunologic tolerance to the kidney allograft developed, allowing withdrawal of all immunosuppressive therapy within 6 months. Immune tolerance of organ transplants has been induced in laboratory animals when persistent mixed blood and immune-cell chimerism has been achieved by infusing hematopoietic cells from the organ donor before or after transplantation of the organ. 1 – 3 The continued presence of the organ donor's immune cells in the recipient's thymus and peripheral lymphoid tissue promotes and maintains immune tolerance by eliminating T-cell clones that can react to alloantigens of the graft. 1 – 3 We have attempted to achieve persistent mixed chimerism and tolerance in humans after transplantation of combined HLA-matched kidney and hematopoietic cells, using a low-intensity conditioning regimen of total . . .

Classical dendritic cells (cDCs) in mice have been divided into 2 major subsets based on the expression of nuclear transcription factors: a CD8 + Irf8 + Batf3 dependent (DC1) subset, and a CD8 - Irf4 + (DC2) subset. We found that the CD8 + DC1 subset can be further divided into CD8 + DC1a and CD8 + DC1b subsets by differences in surface receptors, gene expression, and function. Whereas all 3 DC subsets can act alone to induce potent Th1 cytokine responses to class I and II MHC restricted peptides derived from ovalbumin (OVA) by OT-I and OT-II transgenic T cells, only the DC1b subset could effectively present glycolipid antigens to natural killer T (NKT) cells. Vaccination with OVA protein pulsed DC1b and DC2 cells were more effective in reducing the growth of the B16-OVA melanoma as compared to pulsed DC1a cells in wild type mice. In conclusion, the Batf3-/- dependent DC1 cells can be further divided into two subsets with different immune functional profiles in vitro and in vivo .

Mixed lymphohematopoietic chimerism is a proven strategy for achieving operational transplant tolerance, though the underlying immunologic mechanisms are incompletely understood. A post-transplant, non-myeloablative, tomotherapy-based total lymphoid (TLI) irradiation protocol combined with anti-thymocyte globulin and T cell co-stimulatory blockade (belatacept) induction was applied to a 3-5 MHC antigen mismatched rhesus macaque kidney and hematopoietic cell transplant model. Mechanistic investigations of early (60 days post-transplant) allogeneic immune modulation induced by mixed chimerism were conducted. Chimeric animals demonstrated expansion of circulating and graft-infiltrating CD4+CD25+Foxp3+ regulatory T cells (Tregs), as well as increased differentiation of allo-protective CD8+ T cell phenotypes compared to naïve and non-chimeric animals. mixed lymphocyte reaction (MLR) responses and donor-specific antibody production were suppressed in animals with mixed chimerism. PD-1 upregulation was observed among CD8+ T effector memory (CD28-CD95+) subsets in chimeric hosts only. PD-1 blockade in donor-specific functional assays augmented MLR and cytotoxic responses and was associated with increased intracellular granzyme B and extracellular IFN-γ production. These studies demonstrated that donor immune cell engraftment was associated with early immunomodulation via mechanisms of homeostatic expansion of Tregs and early PD-1 upregulation among CD8+ T effector memory cells. These responses may contribute to TLI-based mixed chimerism-induced allogenic tolerance.

Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-gamma and associated downstream pathways. Comparison of two poles of MS pathology--acute lesions with inflammation versus 'silent' lesions without inflammation--revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common gamma chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.

Treatment of hematologic malignant disease with allogeneic hematopoietic stem cells requires conditioning regimens that carry a substantial risk of acute graft-versus-host disease (GVHD). This study found that a regimen developed in a mouse model sharply reduces the incidence of acute GVHD yet retains potent antitumor activity. This study found that a conditioning regimen developed in a mouse model sharply reduces the incidence of acute GVHD yet retains potent antitumor activity. Allogeneic hematopoietic-cell transplantation with the use of conditioning regimens of nonmyeloablative radiotherapy, chemotherapy, or both to decrease early toxic effects extends the possibility of hematopoietic-cell transplantation to patients older than 50 years and those with coexisting conditions. 1 – 4 However, acute graft-versus-host disease (GVHD) remains a major problem after nonmyeloablative transplantation: acute GVHD (grade II or higher) developed in 20 to 65 percent of the patients in single-center or multicenter trials. 5 – 10 Death due to this complication accounts for approximately 50 percent of the deaths that are not due to a relapse of the neoplasm. 3 , 4 , 10 A new approach to . . .

Dendritic cells (DCs) are powerful antigen presenting cells, derived from bone marrow progenitors (cDCs) and monocytes (moDCs), that can shape the immune response by priming either proinflammatory or tolerogenic immune effector cells. The cellular mechanisms responsible for the generation of DCs that will prime a proinflammatory or tolerogenic response are poorly understood. Here we describe a novel mechanism by which tolerogenic DCs are formed from monocytes. When human monocytes were cultured with CD4 FoxP3 natural regulatory T cells (Tregs) and T helper cells (Th) from healthy donor blood, they differentiated into regulatory DCs (DC ), capable of generating induced Tregs from naïve T cells. DC exhibited morphology, surface phenotype, cytokine secretion, and transcriptome that were distinct from other moDCs including those derived from monocytes cultured with Th or with GM-CSF/IL-4, as well as macrophages (MΦ). Direct cell contact between monocytes, Tregs and Th, along with Treg-derived CTLA-4, IL-10 and TGF-β, was required for the phenotypic differentiation of DC , although only IL-10 was required for imprinting the Treg-inducing capacity of DC . High ratios of Treg:Th, along with monocytes and DC similar in function and phenotype to those induced , were present in human colorectal cancer specimens. Thus, through the combined actions of Tregs and Th, monocytes differentiate into DCs with regulatory properties, forming a positive feedback loop to reinforce Treg initiated immune regulation. This mechanism may contribute to immune tolerance in tissues such as tumors, which contain an abundance of Tregs, Th and monocytes.

Based on preclinical studies, combined kidney and hematopoietic cell transplantation was performed on fully HLA matched and haplotype matched patients at the Stanford University Medical Center. The object of the studies was to induce mixed chimerism, immune tolerance, and complete immunosuppressive drug withdrawal. Tolerance, persistent mixed chimerism, and complete withdrawal was achieved in the majority of fully matched patients. Persistent mixed chimerism and partial withdrawal has been achieved in the haplotype matched patients at present.

Although organ and bone marrow transplantations are life-saving procedures for patients with terminal diseases, the requirement for the lifelong use of immunosuppressive drugs to prevent organ graft rejection and the development of graft versus host disease (GVHD) remain important problems. Experimental approaches to solve these problems, first in preclinical models and then in clinical studies, developed at Stanford during the past 40 years are summarized in this article. The approaches use fractionated radiation of the lymphoid tissues, a procedure initially developed to treat Hodgkin’s disease, to alter the immune system such that tolerance to organ transplants can be achieved and GVHD can be prevented after the establishment of chimerism. In both instances, the desired goal was achieved when the balance of immune cells was changed to favor regulatory innate and adaptive immune cells that suppress the conventional immune cells that ordinarily promote inflammation and tissue injury.