Biomedical subjects

Levi G Ledgerwood

Publications and source records attributed to Levi G Ledgerwood.

4 recordsLinked to original sources

PubMed2005

Combination treatment with donor-specific transfusions and cyclosporine a induces long-term survival of cardiac allografts in miniature Swine.

BACKGROUND: To evaluate whether pretransplant donor-specific transfusions (DST) can induce tolerance to cardiac allografts in large animals, heterotopic cardiac transplants were performed across a class I MHC barrier in inbred miniature swine. METHODS: Experimental animals received two DSTs, each containing 1.4x10 viable peripheral blood mononuclear cells, 14 and 7 days prior to transplantation together with a 12-day course of cyclosporine (CyA) (13 mg/kg IV) starting on postoperative day (POD) 0. RESULTS: Untreated (n=2) and DST-only (n=2) treated control animals rejected between POD 6 and 8. Animals treated with CyA alone (n=3) exhibited graft survival to 53, 52 and 59 days. In contrast, the combination of DST and CyA (n=3) led to stable graft function for >200 days. Long-term survivors maintained peripheral CML response against donor antigen. Following DSTs, the donor-specific proliferative response of CD8+ recipient T cells was significantly increased (P=0.011), and a significant number of CD8+ T cells underwent apoptosis (10.1% on POD 0; 5.2% on POD -14; P=0.04). None of the DST-treated animals developed donor-specific antibodies. CONCLUSIONS: These results are the first to demonstrate the ability of DST to induce operational tolerance to cardiac allografts in large animals, and they suggest that peripheral mechanisms of tolerance mediate this effect.

Acute Disease↗

PubMed2005

Indirect recognition of MHC class I allopeptides accelerates lung allograft rejection in miniature swine.

The role of indirect allorecognition in graft rejection is examined in two experiments using a swine lung transplantation model. First, two swine received class I mismatched grafts without immunosuppression; another two recipients were treated postoperatively with cyclosporine (CsA). These swine exhibited acute and chronic rejection, respectively. All four recipients developed T-cell reactivity to donor-derived class I major histocompatibility complex (MHC) peptides. Second, six swine were immunized with synthetic donor-derived class I allopeptides prior to transplantation. Control groups consisted of nonimmunized recipients (n = 6) and recipients immunized with an irrelevant peptide (n = 3). These recipients all received a 12-day course of post-operative CsA. Swine immunized with allopeptides exhibited accelerated graft rejection, as compared to both control groups (p < 0.01 and p = 0.03, respectively). Within the experimental group, the dominant histologic finding was acute rejection (AR). Obliterative bronchiolitis (OB) was seen in the graft with the longest survival. Both control groups showed a lesser degree of AR, with four out of six nonimmunized swine ultimately developing OB. These studies suggest that indirect allorecognition is operative during lung allograft rejection, and that pre-transplant sensitization to donor-derived MHC allopeptides can accelerate graft rejection.

Acute Disease↗

PubMed2003

Genes, germs, and schizophrenia: an evolutionary perspective.

Literature on schizophrenia and other mental illnesses has emphasized the compatibility of evidence with genetic causation without adequately considering alternative hypotheses of disease causation. Although some studies from the mid-20th century reported associations between certain pathogens and schizophrenia, only recently has the possibility of infectious causation of schizophrenia again become an active focus of research. Infectious causation of schizophrenia is still, however, generally regarded as less well demonstrated than genetic causation. This article evaluates the evidence that has been used to support genetic and infectious causation. Our consideration of infectious causation focuses on the protozoan Toxoplasma gondii but also assesses other pathogens that may contribute to the development of some of the illnesses currently categorized as schizophrenia. Although evidence generally accepted as demonstrating genetic causation can be readily explained by hypotheses of infectious causation, some of the evidence implicating infectious causation cannot be similarly explained by genetic causation. This asymmetry indicates that a scientific approach to the causation of schizophrenia needs to put a greater emphasis on tests that distinguish hypotheses of genetic causation from those of infectious causation.

Animals↗

PubMedDate not supplied

Sphingosine 1-phosphate receptor modulators: a new class of immunosuppressants.

In this review, we summarize how FTY720 came from the lab bench to the bedside by examining its structural similarities to natural occurring sphingosine analogues, the mechanism of action, and clinical applicability to not only transplantation but also autoimmune, oncological, and neurobiological fields. FTY720, a sphingosine 1-phosphate (S1P) analogue, promotes the survival of human and animal allografts by sequestering T lymphocytes within peripheral lymphoid tissue. The mechanism of sequestration is three-fold: (1) T lymphocytes are driven into peripheral lymph nodes in a chemokine dependent manner by FTY720; (2) FTY720 downregulates sphingosine 1-phosphate receptors (S1PRs) on the T lymphocyte surface, rendering it unable to migrate along a S1P gradient; and (3) FTY720 closes stromal gates on the abluminal side of the lymphatic endothelium. Future areas of investigation include developing S1P analogues that have specific agonist binding to S1PRs avoiding side effects seen in non-specific binding.

Animals↗