Biomedical subjects

Jeffrey Schechner

Publications and source records attributed to Jeffrey Schechner.

4 recordsLinked to original sources

PubMed2005

Malignant transformation of human cells by constitutive expression of platelet-derived growth factor-BB.

Platelet-derived growth factors (PDGFs) comprise a family of growth factors strongly implicated in human oncogenesis. A number of human tumors overexpress PDGF family members or have translocations activating PDGF receptors. Whereas the epidemiologic evidence implicating PDGF in human tumors is strong, malignant transformation of human cells by overexpression of PDGF has not been demonstrated. We have previously developed a human cell line by the sequential introduction of large T cells and telomerase, and we have demonstrated that these cells express functionally active PDGF receptor (PDGFR) beta. In order to determine whether growth factor-mediated transformation of human cells could occur, these cells were transduced with a retrovirus encoding PDGF-BB. Constitutive expression of PDGF-BB led to malignant transformation in nude mice. This is the first demonstration of constitutive signaling causing malignant transformation of human cells. Some of the changes that occur because of constitutive growth factor expression can be reversed by the clinically approved tyrosine kinase inhibitor Glivec, whereas other changes are not reversible by tyrosine kinase inhibitors. Our model allows the assessment of epigenetic changes that occur during human carcinogenesis. In addition, these studies provide insight into the clinical failure of tyrosine kinase inhibitors as monotherapy for advanced malignancy.

Animals↗

PubMed2004

Endothelial cells present antigens in vivo.

BACKGROUND: Immune recognition of vascular endothelial cells (EC) has been implicated in allograft rejection, protection against pathogens, and lymphocyte recruitment. However, EC pervade nearly all tissues and predominate in none, complicating any direct test of immune recognition. Here, we examined antigen presentation by EC in vivo by testing immune responses against E. coli beta-galactosidase (beta-gal) in two lines of transgenic mice that express beta-gal exclusively in their EC. TIE2-lacZ mice express beta-gal in all EC and VWF-lacZ mice express beta-gal in heart and brain microvascular EC. RESULTS: Transgenic and congenic wild type FVB mice immunized with beta-gal expression vector DNA or beta-gal protein generated high titer, high affinity antisera containing comparable levels of antigen-specific IgG1 and IgG2a isotypes, suggesting equivalent activation of T helper cell subsets. The immunized transgenic mice remained healthy, their EC continued to express beta-gal, and their blood vessels showed no histological abnormalities. In response to beta-gal in vitro, CD4+ and CD8+ T cells from immunized transgenic and FVB mice proliferated, expressed CD25, and secreted IFN-gamma. Infection with recombinant vaccinia virus encoding beta-gal raised equivalent responses in transgenic and FVB mice. Hearts transplanted from transgenic mice into FVB mice continued to beat and the graft EC continued to express beta-gal. These results suggested immunological ignorance of the transgene encoded EC protein. However, skin transplanted from TIE2-lacZ onto FVB mice lost beta-gal+ EC and the hosts developed beta-gal-specific antisera, demonstrating activation of host immune effector mechanisms. In contrast, skin grafted from TIE2-lacZ onto VWF-lacZ mice retained beta-gal+ EC and no antisera developed, suggesting a tolerant host immune system. CONCLUSION: Resting, beta-gal+ EC in transgenic mice tolerize specific lymphocytes that would otherwise respond against beta-gal expressed by EC within transplanted skin. We conclude that EC effectively present intracellular "self" proteins to the immune system. However, antigen presentation by EC does not delete or anergize a large population of specific lymphocytes that respond to the same protein following conventional immunization with protein or expression vector DNA. These results clearly demonstrate striking context sensitivity in the immune recognition of EC, a subtlety that must be better understood in order to treat immune diseases and complications involving the vasculature.

Animals↗

PubMed2002

Transimmunization and the evolution of extracorporeal photochemotherapy.

We are now aware that extracorporeal photopheresis (ECP) - in which a patient's leukocytes are isolated, passed through an ultrathin clear plastic plate, and exposed to 8-methoxypsoralen (8-MOP) and ultraviolet A light prior to reinfusion - is a simple and efficient dendritic cell (DC) therapy and the first FDA approved selective immunotherapy for cancer. DCs, as the most effective antigen presenting cells (APCs), are central to many ongoing efforts to stimulate immune responses to cancer cells. Moreover, ECP has not only demonstrated efficacy in the treatment of a T cell malignancy--namely cutaneous T-cell lymphoma (CTCL)--but also in treatment of oligoclonal T-cell-mediated diseases such as graft-versus-host-disease (GVHD) and organ transplant rejection. Recent advances in the understanding of DC/T-cell interactions provide insight into how ECP-induced DCs (EI-DCs) can be utilized to stimulate specific T-cell (i.e. anti-tumor) responses, or down-regulate a pre-existing potent T-cell response. The mechanism of this apparent paradox of EI-DC functionality is likely dependent on several fundamental principles: (1) the status of existing in vivo T-cell reactions, (2) the temporal stage of EI-DC differentiation, and (3) the affinity of the available repertoire of T-cell receptors (TCRs) for the antigen(s) in question. Further investigation into DC/T-cell interactions will help to shape the future of ECP and the ability to optimize this therapy for the desired immune effect. To this end, we are developing and testing Transimmunization to replace conventional ECP.

Dendritic Cells↗

PubMed2002

Red skin re-read.

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Arteriovenous Anastomosis↗