Gender	Male
E-mail	constantin.bona@mssm.edu
Education and Training	D.C. Sci., University of Paris
	M.D., University of Bucharest

Education and Training	D.C. Sci., University of Paris
	M.D., University of Bucharest

virology, immunology
For the future years, my laboratory has two major research goals. The first is related to the study of the enhancement of anti-viral immunity by using genetically or enzymatically engineered Igs and the second is related to study the effect of mature lymphocytes and skin immunity defect on TSK syndrome and the complementation of TSK mutation by collagen I and V defective genes. Advances in biotechnology have ushered in a new era of vaccine development. These developments are based on the utilization of peptides corresponding to protective epitopes, recombinant proteins, viral or bacteria vectors, naked DNA etc. Two promising avenues of research are maternal immunization which may confer protection to infants and neonatal immunization which may confer protection to children. During the past year, we have used engineered immunoglobulins as a delivery system for viral B and T cell epitopes. The overall goal is to use the influenza virus system to evaluate the effects of maternal and neonatal immunization of two types of new vaccines: antigenized Ig and naked DNA. Our aims are to understand the basic immune mechanisms of maternal and neonatal immunization with antigenized Ig and naked DNA which may led to protective response against influenza virus. In theses studies, we will use: a) genetically engineered Ig in which a B cell epitope was grafted in CDR2 and a T cell epitope in CDR3. b) Enzymatically engineered Ig in which the viral epitopes were specifically conjugated to sugar moiety of Ig molecule and c) Plasmids expressing influenza virus NP or HA genes. Transgenic mice expressing a TCR specific for influenza virus hemagglutinin dominant peptide will be used to study the molecular mechanisms of tolerance.

The second goal is to examine the development of tight skin syndrome in congenitally defective mice in lymphocyte receptor, skin immunity and in fibrillinogenesis. This study will be carried out on backcross progeny obtained by the crossing of TSK mice with: a) RAG2-/- and Ig-/- mice obtained by targeted deletion. The RAG2-/- mice lack both T and B mature lymphocytes, whereas, Ig-/- mice only B lymphocytes. b) vit/vit mice bearing a mutation responsible for the genetic defect in skin immunity. c) MOV13 mice which have complete transcriptional block of a1 collagen gene and pNA25 mice which have a defect of collagen type V gene. This study will provide definitive proof for the role of the immune system in TSK scleroderma-like syndrome and will provide information on the complementation of TSK gene defect by collagen defective genes. The ultimate goal of this project is to clone the TSK gene and use it to fish out a human gene which may be involved in scleroderma.

Saito S, Nishimura H, Brumeanu T, Casares S, Stan AC, Honjo T, Bona C. Characterization of mutated protein encoded by partially duplicated fibrillin-1 gene in tight skin (TSK). Mol Immunol 1999 Feb; 36(3): 169-176.

Tan FK, Arnett FC, Antohi S, Saito S, Mirarchi A, Spiera H, Sasaki T, Shoichi O, Takeuchi K, Pandy JP, Silver RM, LeRoy C, Postlethwaite AE, Bona C. Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin-1, in patients with scleroderma. J Immunol 1999 Jul; 163(2): 1066-1072.

Stan AC, Radu D, Casares S, Bona C, Brumeanu T. Antineoplastic efficacy of doxorubicin enzymatically assembled on galactose residues of a monoclonal. Cancer Res 1999 Jan; 59(1): 115-121.

Casares S, Zong C, Radu D, Miller A, Bona C, Brumeanu T. Antigen-specific signaling by a soluble, dimeric peptide/major histocompatibility complex class II/Fc. J Exp Med 1999 Aug; 190(4): 543-553.

Casares S, Bona C, Brumeanu T. Enzymatically mediated engineering of multivalent MHC class II-peptide chimeras. Protein Eng 2001; 14: 195-200.

Stan AC, Casares S, Brumeanu T, Klinman DM, Bona C. CpG motifs of DNA vaccines induce the expression of chemokines and MHC class II molecules on myocytes. Eur J Immunol 2001 Jan; 31: 301-310.

Casares S, Stan AC, Bona C, Brumeanu T. Antigen-specific downregulation of T cells by doxorubicin delivered through a recombinant MHC II--peptide chimera. Nat Biotechnol 2001 Feb; 19: 142-147.

Brumeanu T, Bona C, Casares S. T-cell tolerance and autoimmune diabetes. (review) Int Rev Immunol 2001; 20(2): 301-31.

Casares S, Bona C, Brumeanu T. Modulation of CD4 T cell function by soluble MHC II-peptide chimeras. Int Rev Immunol 2001 Oct; 20(5): 547-73.

Casares S, Bona CA, Brumeanu TD. Immunoregulation of antigen-specific T cell by MHC-peptide chimeras. Int. Rev. Immunol 2001; 20: 547-574.