SUMMARY REPORTS OF EXCHANGE SCIENTISTS
(1) Takashi Fujita
Tokyo Metropolitan Institute of Medical Science
SPONSOR AND HOST INSTITUTION
Dr. Garry P. Nolan, Stanford University
Dr. David Baltimore, The Rockefeller University
Dr. Raul Andino, Gladstone Institute of Virology and Immunology
DATES OF VISITS: August 28Å[September 12, 1993
SUMMARY OF ACTIVITIES:
Stanford University:
I gave a lecture on studies of gene regulation in cytokine system. The lecture was followed by discussion with scientists in the department. Following subjects were mainly discussed:
1) Expression of the candidate proto-oncogene product BCL-3 in normal and developing tissues.
2) Posttranslational modification of BCL-3 (phosphorylation) and its functional regulation.
3) Future collaborative research on biological functions of BCL-3. (bcl-3 gene knock out; overexpression of "dominant negative" bcl-3 mutant)
Rockefeller University:
Following subjects were discussed with Dr. D. Baltimore and his colleagues:
1) Phenotype of the mouse that lacks NFB 1 gene encoding one of the subunits of transcription factor NF-KB.
2) Collaborative research on BCL-3 wild type and mutant proteins.
3) We discussed on the usefulness of "two hybrid system" recently developed to demonstrate protein-protein interactions in cells.
4) Technical improvement to express biologically active nuclear protein in soluble fraction in mammalian cells.
Gladstone Institute of Virology and Immunology (UCSF):
I gave a lecture on gene regulation in the NF-KB scientists of the institute: system and discussed with several scientists of the institute:
1) Dr. Andino: HIV vaccine using polio virus as vector.
2) Dr. W. Green: We discussed the mechanism of transcriptional activation by tax protein encoded by HTLV-1.
3) Dr. A. Frankel: Physical interaction between tat and tar of HIV.
(2) Kouji Matsushima
Cancer Research Institute, Kanazawa University
SPONSOR AND HOST INSTITUTION:
Dr. Joost J. Oppenheim, Division of Cancer Treatment
National Cancer Institute
DATE OF VISIT: January 1Å[15, 1994
SUMMARY OF ACTIVITIES:
- molecular analysis of cytokine network involved in causing cancer associated cachexia: Cancer associated cachexia determines quality of life of cancer patients. The goal of this study is identifying bona fide cachectin (cachexia inducing substance) in tumor bearing hosts and revealing molecular mechanisms of cachectin production in vivo. Mouse colon carcinoma cell line, colon 26 was chosen as a model tumor causing cachexia in mice Clone 20 (cachectic clone) caused cachexia in 10 days in Balb/c nu/nu and SCID as well as normal Balb/c mice. This observation suggests that no specific immune reaction triggered by tumor-associated antigen is involved in causing cachexia by colon 26.
Northern blotting analysis of cytokine gene expression in tumors of clone 20 and clone 5 (non-cachectic clone) revealed that IL 1, LIF, and TGFbeta were constitutively expressed in both clones. IL 6 was selectively expressed in clone 20, whereas IL 1 receptor antagonist was expressed in clone 5. Since both clone cells responded to IL 1 to produce IL 6 in vitro, IL 1 receptor antagonist produced simultaneously at clone 5 tumor site might block IL 1 activity to inhibibit IL 6 production. Through the discussion with Dr. Oppenheim, importance of identification of cytokine producing cells was pointed out. IL 1 receptor antagonist cDNA transfer to clone 20 was also suggested.
- Pathophysiological roles of tumor infiltrating leukocytes: Although the presence of host leukocytes in the context or at the periphery of neoplastic tumors has long been recognized, the biological and clinical significance of tumor infiltrating leukocytes remains to be established. Since our discovery and molecular cloning of interleukin 8, the existence of leukocyte chemotactic cytokine superfamily (chemokine) have been unraveled. We examined the effect of localized secretion of chemokines on tumor growth. The cDNAs for IL 8, MIP1, and MCAF were introduced via mammalian expression vector into Chinese hamster ovarian cells, and the ability of the transfectants to form tumors in vivo was assessed in nude mice. IL 8 and MIP1cDNA introduction strongly suppressed tumor growth. Anti-tumor activity was correlated with the number of neutrophils infiltrated into tumor sites 48 hours after the injection of transfectants. The effects of constitutive production of chemokines on cancer cachexia and tumor metastasis are also under investigation.
(3)Nagahiro Minato
Department of Immunology and Cell Biology
Faculty of Medicine, Kyoto University
SPONSOR AND HOST INSTITUTION:
Dr. Samuel Strober, Department of Medicine
Stanford University
Dr. Jack L. Strominger, Department of Biochemistry and
Molecular Biology, Harvard University
Dr. Barry R. Bloom, Department of Immunology and Cell Biology
Albert Einstein College of Medicine
DATES OF VISITS: December 4–18, 1993
SUMMARY OF ACTIVITIES:
The major purpose of my visiting the laboratories in the United States was to exchange the most recent information about research on immune recognition and to explore the possibility for the research collaboration. My first visit was to the lab of Dr. S. Strober at Stanford University. Dr. Strober's group has been working on a unique T cell subset involved in the regulation of bone marrow transplantation, while we have been studying the T cells in the hematopoietic tissues. In spite of the quite distinct approaches and independent motives, we reached the common consensus that we were dealing with very similar, if not the same, unique immunological phenomena. In the very intensive discussion with his group, it became evident that the T cell receptors (TCR) of their supressor T cell clones of GVH and those of our MHCunrestricted killer T cell clones shared the consensus amino acid sequences in the antigen recognition sites, implying that these apparently distinct T cells had very similar antigen recognition modes. Unlike regular T cells, both types of T cell subsets seem to recognize autologous antigens expressed on proliferating cells in MHC-unrestricted fashion. To further investigate the very unique biological roles these T cell subsets might play in the control of normal, as well as transformed proliferating cells, we agreed to start research collaboration, including the exchange of experimental materials such as cloned T cells and monoclonal antibodies.
I then visited Dr. J. Strominger’s lab at Harvard University, where I presented our recent advances on the canonical T cell receptor and its possible ligand, 4F2 antigen.
Human 4F2 antigen has been first described in Dr. Strominger's lab as an activation antigen; and we have recently cloned murine 4F2 cDNA as a possible ligand for MHCunrestricted T cells. We had a very fruitful discussion on the biological functions of this very interesting molecule and agreed to keep exchanging information. I am particularly grateful for Dr. Strominger’s continuous encouragement and critical suggestions for our work on the T cells with canonical TCR and MHC-unrestricted recognition.
Finally, I visited Dr. B. R. Bloom at Albert Einstein College of Medicine, where I did my post doctorate from 1977 to 1980. In Dr. Bloom's lab, we had a very long and extensive discussion on our CD3+4-8!
!
!T cells and their CD 3+4-8!!
!T cells, both of which apparently recognize the unique antigens independent of MHC antigens, as well as the basic conceptual issues on such T cells. Also, we exchanged the most recent information on the genome projects on the pathogenic bacilli such as mycobacterium, which is certainly becoming one of the most important issues in medical science. Dr. Bloom's lab is one of the most active l p aces in this field, and I agreed to collaborate with his group, particularly in the personal exchange at the post doctorate level. I think my trip was very fruitful in exchanging informal information on related research projects and setting up new collaborations. These should certainly help not only to improve our own research projects, but also to facilitate mutual, very productive scientific interactions between the laboratories in two countries.