Costimulation couture: a designer approach to regulating autoimmunity.

Negative or inhibitory costimulatory pathways regulate T cell activation and play a role in peripheral tolerance. Targeting these pathways harnesses the physiologic mechanisms of regulating autoimmunity and could prove beneficial for the therapy of autoimmune diseases. However, attempts at targeting these pathways have been fraught with difficulties.

Persistence of antigen is required to maintain transplantation tolerance induced by genetic modification of bone marrow stem cells.

Genetic modification of hematopoietic stem cells (HSCs) resulting in a state of molecular chimerism can be used to induce donor-specific tolerance to allografts. However, the requirements for maintaining tolerance in molecular chimeras remain unknown. Here, we examined whether long-term expression of a retrovirally encoded alloantigen in hematopoietic cells is required to maintain donor-specific tolerance in molecular chimeras.

Tissue expression of PD-L1 mediates peripheral T cell tolerance.

Programmed death 1 (PD-1), an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. PD-1 has two ligands: PD-1 ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells; and PD-L2, which is restricted to macrophages and dendritic cells. To investigate whether PD-L1 and PD-L2 have synergistic or unique roles in regulating T cell activation and tolerance, we generated mice lacking PD-L1 and PD-L2 (PD-L1/PD-L2(-/-) mice) and compared them to mice lacking either PD-L.

Induction of alloreactive CD4 T cell tolerance in molecular chimeras: a possible role for regulatory T cells.

Induction of molecular chimerism following reconstitution of mice with autologous bone marrow cells expressing a retrovirally encoded allogeneic MHC class I Ag results in donor-specific tolerance. To investigate the mechanism by which CD4 T cells that recognize allogeneic MHC class I through the indirect pathway of Ag presentation are rendered tolerant in molecular chimeras, transgenic mice expressing a TCR on CD4 T cells specific for peptides derived from K(b) were used. CD4 T cells expressing the transgenic TCR were detected in mice reconstituted with bone marrow cells transduced with retroviruses carrying the gene encoding H-2K(b), albeit detection was at lower levels than in mice receiving mock-transduced bone marrow.

Novel insights into the mechanism of action of FTY720 in a transgenic model of allograft rejection: implications for therapy of chronic rejection.

FTY720 is a high-affinity agonist at the sphingosine 1-phosphate receptor 1 that prevents lymphocyte egress from lymphoid tissue and prolongs allograft survival in several animal models of solid organ transplantation. In this study we used a recently developed adoptive transfer model of TCR transgenic T cells to track allospecific CD4+ T cell expansion and trafficking characteristics, cytokine secretion profiles, and surface phenotype in vivo in the setting of FTY720 administration. We report that FTY720 administration had no effect on alloantigen-driven T cell activation, proliferation, acquisition of effector-memory function, or T cell apoptosis.

Inhibition of CD26 peptidase activity significantly improves engraftment of retrovirally transduced hematopoietic progenitors.

It has previously been shown that inhibition of CD26 (DPPIV/dipeptidylpeptidase IV) peptidase activity improves homing of hematopoietic stem cells (HSCs) to the bone marrow and increases engraftment efficiency. Here, we demonstrate that treatment of retrovirally transduced mouse bone marrow cells with the tri-peptide Diprotin A (Ile-Pro-Ile), a specific inhibitor of CD26, significantly enhances engraftment of retrovirally transduced HSCs. Treatment of transduced bone marrow cells with Diprotin A permitted long-term expression of a retrovirally encoded MHC class I gene on multiple hematopoietic cell lineages after transplantation of a suboptimal number of transduced cells.

T-cell costimulatory pathways in allograft rejection and tolerance.

A key factor driving the underlying pathyphysiology of "chronic rejection" in organ transplantation is a persistent T cell-mediated alloimmune response. Members of both the B7 family (including CD28 and CTLA4) and the tumor necrosis factor (TNF) family, in which the CD40-CD154 pathway is preeminent, play key roles in the T cell response following alloantigen presentation. "Positive" costimulatory molecules promote full T cell activation, whereas a subgroup of costimulatory molecules delivers "negative" costimulatory signals that function to downregulate alloimmune responses.

The bihemispheric posterior inferior cerebellar artery.

Rarely, a solitary posterior inferior cerebellar artery (PICA) will supply both cerebellar hemispheres. We report four cases of this variant. We present a retrospective review of clinical information and imaging of patients undergoing angiography at our institution to identify patients with a bihemispheric PICA.

Requirements for induction and maintenance of peripheral tolerance in stringent allograft models.

Peripheral tolerance can be achieved in many but not all murine allograft models. The requirements for controlling more aggressive immune responsiveness and generating peripheral tolerance in stringent allograft models are unknown. Understanding these requirements will provide insight toward ultimately achieving tolerance in humans, which are also resistant.

PEX-producing human neural stem cells inhibit tumor growth in a mouse glioma model.

A unique characteristic of neural stem cells is their capacity to track glioma cells that have migrated away from the main tumor mass into the normal brain parenchyma. PEX, a naturally occurring fragment of human metalloproteinase-2, acts as an inhibitor of glioma and endothelial cell proliferation, migration, and angiogenesis. In the present study, we evaluated the antitumor activity of PEX-producing human neural stem cells against malignant glioma.

The influence of natural antibody specificity on antigen immunogenicity.

The natural antibody repertoire in humans, apes and Old World primates is distinct from the repertoire of all other placental mammals, and encodes antibodies specific for the carbohydrate epitope Galalpha1-3Galbeta1-4GlcNAc-R (alphaGal). Here, we examined whether conjugating antigens to the alphaGal epitope can augment their immunogenicity in alpha(1,3)galactosyltransferase knockout mice (GT0 mice) which, like humans, produce alphaGal-specific antibodies. Immunization of GT0 mice with BSA conjugated to alphaGal (alphaGal-BSA) led to significant production of anti-BSA IgG antibodies without the need for adjuvant.

Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor.

The transplantation of neural stem cells (NSCs) offers a new potential therapeutic approach as a cell-based delivery system for gene therapy in brain tumors. This is based on the unique capacity of NSCs to migrate throughout the brain and to target invading tumor cells. However, the signals controlling the targeted migration of transplanted NSCs are poorly defined.

A critical role for the programmed death ligand 1 in fetomaternal tolerance.

Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti.

Induction of donor-specific tolerance in sublethally irradiated recipients by gene therapy.

Donor-specific transplantation tolerance can be established through the induction of molecular chimerism following reconstitution of lethally irradiated mice with autologous bone marrow expressing retrovirally transduced allogeneic MHC antigens. Here, we set out to define nonmyeloablative host conditioning regimens that would allow for establishment of molecular chimerism and the induction of donor-specific tolerance. Recipient mice received various doses of whole-body irradiation, together with costimulatory blockade using anti-CD154 monoclonal antibody prior to reconstitution with syngeneic bone marrow cells transduced with retroviruses carrying the gene encoding H-2K(b).

Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo.

Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear. This study examined the role of these inhibitory pathways in regulating CD28-dependent and CD28-independent CD4 and CD8 alloreactive T cells in vivo.

Preventing autoimmune diabetes through gene therapy.

Extract: Type 1 diabetes is an autoimmune disease in which an individual develops T cells that are able to destroy insulin-producing beta cells in the pancreas. Type 1 diabetics require life-long treatment with exogenous insulin for survival. Susceptibility to type 1 diabetes is influenced by both genetic and environmental factors.

Transplantation tolerance in pediatric recipients: lessons and challenges.

Clinical transplantation tolerance has remained an elusive goal in the 50 yr since it was first described in experimental animals. Greater understanding of the molecular mechanisms responsible for allorecognition have allowed for the development of promising immunosuppressive strategies that may bring us closer to reproducible induction of tolerance; consideration of past successes and failures from both clinical and basic science is required to define future challenges facing this field. This article reviews mechanisms of self and transplantation tolerance, translation of basic science research to clinical protocols in animals and human beings, the changing role of immunosuppression, complications following tolerance induction and controversies surrounding the choice of patients for tolerance trials with a focus on issues relevant to pediatric patients.

CD70 signaling is critical for CD28-independent CD8+ T cell-mediated alloimmune responses in vivo.

The inability to reproducibly induce robust and durable transplant tolerance using CD28-B7 pathway blockade is in part related to the persistence of alloreactive effector/memory CD8(+) T cells that are less dependent on this pathway for their cellular activation. We studied the role of the novel T cell costimulatory pathway, CD27-CD70, in alloimmunity in the presence and absence of CD28-B7 signaling. CD70 blockade prolonged survival of fully mismatched vascularized cardiac allografts in wild-type murine recipients, and in CD28-deficient mice induced long-term survival while significantly preventing the development of chronic allograft vasculopathy.

Transplantation tolerance. A complex scenario awaiting clinical applicability.

Organ transplantation is now firmly established as the therapy of choice for end-stage organ failure. Specific immunological tolerance of transplant recipients towards their foreign organ or tissue grafts is a goal that has been sought by transplant biologists for almost 50 years following the original description of the phenomenon in experimental animals by Medawar and colleagues. Since that time, a wealth of experimental data has accumulated relating to strategies for extending allograft survival and function.

The roles of the new negative T cell costimulatory pathways in regulating autoimmunity.

The B7 family of T cell costimulatory molecules has recently acquired several new members. Some of these are activating while others are inhibitory. In this review, we will focus on the novel inhibitory pathways with particular emphasis on the PD-1:PD-L pathway.

Histologic measures of angiogenesis in human primary brain tumors.

Quantitative determination of the degree of vascularity has been shown to be independently prognostically significant in many human tumor types. In particular, tumor vascularity has known importance in astrocytomas, in which endothelial proliferation is a criterion for anaplasia in many grading schemes. This chapter summarizes the known associations of quantitated microvessel parameters obtained from histologic sections of human brain tumors with clinical outcome, or other pathobiologic factors that have been examined.

Antiangiogenic therapy by local intracerebral microinfusion improves treatment efficiency and survival in an orthotopic human glioblastoma model.

Targeting active angiogenesis, which is a major hallmark of malignant gliomas, is a potential therapeutic approach. For effective inhibition of tumor-induced neovascularization, antiangiogenic compounds have to be delivered in sufficient quantities over a sustained period of time. The short biological half-life of many antiangiogenic inhibitors and the impaired intratumoral blood flow create logistical difficulties that make it necessary to optimize drug delivery for the treatment of malignant gliomas.

Wound fluid bacterial levels exceed tissue bacterial counts in controlled porcine partial-thickness burn infections.

In the present study, an established controlled burn wound model was used to test the hypothesis that controlled surface contamination with is capable of generating a noninvasive method for the creation of a reproducible deep tissue burn wound infection. Using a liquid tight-wound chamber in Yorkshire pigs, partial-thickness burns were inoculated with saline-immersed for 24 hours. Noninoculated burns and unwounded skin immersed in normal saline served as controls.

Intraoperative magnetic resonance for the surgical treatment of lesions producing seizures.

Seizures are a major presenting feature of several non-neoplastic cerebral lesions. We reviewed the experience at the Brigham and Women's Hospital, Boston, on the surgical management of benign intracerebral lesions presenting with seizures with intraoperative magnetic resonance imaging (iMRI) guidance. Our aim was to demonstrate that this is an effective and efficient treatment for these lesions.