1981 BIOLOGY AND DIAGNOSIS PROGRAM AREA SUMMARY REPORTS OF EXCHANGE SCIENTISTS

SUMMARY REPORTS OF EXCHANGE SCIENTISTS

(1) Ulf R. Rapp, M.D.,
Viral Pathology Section, Laboratory of Viral Carcinogenesis, National Cancer Institute, FCRC, Bethesda, Maryland, USA

Dates of Visit: February 15 to February 27, 1982
Host:
Dr. Yoji Ikawa, Cancer Institute, Tokyo

Summary of Activities:

			During my stay in Japan I visited the following and presented seminars on "Use of MuLV for the Transduction of Cell Derived Tumor Genes".
		Feb. 18 (Thu):	National Cancer Center Institute, Tokyo Discussions with Dr. S. Nishimura
		19 (Fri):	Institute of Virus Research, Kyoto Univ., Kyoto Discussions with Dr. M. Hatanaka
		24 (Wed):	Faculty of Pharmaceutical Science, Okayama University, Okayama Discussions with Dr. M. Futai
		27 (Sat):	Institute of Medical Science, University of Tokyo, Tokyo

This visit was arranged together with Dr. Yoji Ikawa, Chief, Department of Viral Oncology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan and the US-Japan Cooperative Cancer Research Program. Its main purpose was an exchange of expertise in the area of tumorgene-transduction with retrovirus.
Upon arrival in Tokyo on February 15, 1982, I visited Dr. Ikawa's laboratory where I was engaged in discussions with his staff, the setting up of collaborative projects and the presentation of research findings for the next 4 days. Specifically, we have developed during this time a collaboration concerning the cell surface receptor binding specificity of spleen focus forming virus, comparing it to that of another MCF class MuLV isolated in my laboratory which has an apparent specificity for transformation of epithelial lung cells. We also reviewed the progress of our work with a new histiocytoma inducing virus. The tumorgene DNA from this virus will be used by Dr. Ikawa for the screening of human tumor cell lines. Another area of collaboration concerns the expression of endogenous human retrovirus in a collection of human tumor cell lines which Dr. Ikawa has. For this, molecularly cloned probes will be used that were developed in the Viral Pathology Section. We will also continue experiments aimed at the rescue of expressed tumor genes from these same cell lines.
During my time in Dr. Ikawa's lab I met Dr. M. Hatanaka, who heads a department in the Institute for Virology in Kyoto. I accompanied him for a period of 3 days for discussions with his research group as well as with Drs. Ito, Hinuma, Ishimoto and Niwa. Upon returning to Tokyo, I continued my work in Dr. Ikawa's laboratory and also spent some time at the National Cancer Center and at the Medical and Scientific Institute of Tokyo University. At the National Cancer Center I had very stimulating discussions with several members of its faculty, especially Dr. Nishimura and his group. In the Medical and Scientific Institute, I met a number of scientists who I had previously become acquainted with in the United States and had a very productive interaction especially with Dr. Kuroki and Dr. Oda.
Japan for me was not only impressive scientifically, I also had the opportunity to experience repeatedly the kind hospitality of its people and could develop a feeling for their way of life. I was very happy to have this opportunity because it helped me understand better my Japanese friends and because it should make it easier for me now to communicate with visiting fellows and scientists from Japan who might join my lab here in the future.

(2) Ira Pastan
Laboratory of Molecular Biology
National Cancer Institute

Sponsor and Host Institution:
Shigetada Nakanishi, Kyoto University
Dates of Visit: November 2-8, 1982

Summary of Activities
The U.S.-Japan meeting took place at the Kyoto International Conference Hall in Kyoto, Japan, on November 5-7. The American participants were Dr. Ira Pastan, Dr. Sam Barondes, Dr. Kenneth Yamada, Dr. Weissman, and Dr. Luis Glaser. The Japanese participants are listed on the enclosed schedule. Each speaker spoke for 30 minutes with about 20 minutes of discussion. The meeting focused on cell-cell interactions. It began with discussions of primitive cells such as hydra and slime molds and progressed to studies on cancer cells and at the end on cancer cells isolated from patients. There was considerable discussion about adhesive factors that might be abnormal in cancer cells and the identification of new recognition factors and adhesive factors. The discussions were lively and clearly benefited both the U.S. and Japanese participants. A new feature of the meeting was the presentation of public lectures to students and other faculty at Kyoto University and the surrounding universities who could not participate in the symposium. Drs. Yamada, Weissman, Glaser and Pastan presented a public lecture on the last afternoon of the meeting that was very well attended.

(3)Samuel Barondes
National Cancer Institute

Sponsor and Host Institution:
Ikuo Takeuchi, Kyoto University
Dates of Visit: November 2-8, 1982

Summary of Activities
Upon my arrival in Osaka, Japan, in the evening of November 2, I was met by Dr. Nakanishi. The following day, November 3, I visited him in his laboratory at Kyoto University where we spent most of the day discussing our mutual interest in solving problems dealing with recombinant DNA. On November 4, Dr. I. Takeuchi and I were together in his Laboratory of Botany and Biophysics exchanging information regarding our work regarding cell-cell adhesion and slime mold development.

(4) Irving L. Weissman
Stanford University Medical Center

Sponsor and Host Institution:
Yoji Ikawa, Japanese Foundation for Cancer Research
Dates of Visit: Oct. 26-Nov. 9, 1981

Summary of Activities
I was a visiting scientist to several laboratories and to a group presentation to the Japanese immunologists. First, after arrival in Tokyo, I went to Osaka, where I participated in a mini-symposium on B lymphocyte maturation, and spent an extra day discussing scientific interactions with Drs. Honjo, Hamaoka, Kishimoto, and Yamamoto. Following that two-day visit I traveled to Kyoto, where Dr. Tomio Tada included me as a participant and speaker in a symposium on immune regulation for immunologists from all over Japan, held on October 30th and 31st. After that, I attended the symposium which was organized by Drs. Pastan and Ikawa. Finally, I visited the laboratory of Dr. Hiroshi Watanabe, Chief of the Shimoda Marine Research Center, Shimoda Bay, Japan, to discuss our mutual interests and potential collaborations on the cell to cell interactions carried out by the highest invertebrates, the colonial tunicates. There we developed models of allorecognition by these primitive chordates that might involve lymphocyte-like immunity, and its importance in the evolutionary development of the major histocompatibility complex.

(5) Masatoshi Takeichi
Kyoto University, Faculty of Science, Department of Biophysics

Sponsor and Host Institution:
Dr. Kenneth M. Yamada, National Cancer Institute, Laboratory of Molecular Biology, Membrane Biochemistry Session.
Dates of Visit: June 20-July 10, 1981

Summary of Activities:
The purpose of this short visit to the laboratory of Dr. K. M. Yamada and other laboratories was to learn the recent progress in the research field concerning the adhesion and recognition of cancer cells, and also discuss the future collaboration between Japan and U.S. in this research field.
Actually I could learn a plenty of latest findings and techniques which are directly related to my research subjects through the discussion in the above laboratories. I also gave seminars in several laboratories to discuss my recent findings. This was particularly useful for planning our future collaborations which we found are most important for enhancing the cancer cell biology. I also attended to Gordon Conference, the session for cell adhesion, recognition and migration, and learned many important ideas which should be immediately incorporated into our study on the cancer cell behavior in Japan.

Overall Assessment of the Program

1.	Has the Program assisted you in achieving your research objectives? Explain. Yes. I learned no doubt a lot of important ideas which are very useful for achievement of my research subjects.
2.	How can progress in your research effort be enhanced through this Program? Do you plan to continue your collaboration? I will keep contacts with scholars whom I met in this exchange program, and also plan to collaborate with some of them in the near future.
3.	Please provide information indicating how your efforts have contributed to the progress of the NCI-Japan Cancer Program. My contribution to this program is no other than that I could exchange a number of important information on my scientific field with scholars in U.S.

(6) Toshiyuki Hamaoka
Institute for Cancer Research, Osaka University Medical School, Fukushima, Fukushimaku, Osaka 553, Japan

Sponsor and Host Institution:
Dr. Mark I. Greene; Harvard Medical School, Boston
Dr. Richard J. Hodes; National Cancer Institute, Bethesda
Dr. Christopher S. Henney; Fred Hutchinson Cancer Research Center, Seattle.
Dates of Visit: May 19-June 5, 1981

Summary of Activities:
Fred Hutchinson Cancer Research Center: Discussion about the relating fields with Drs. C.S. Henney, S. Gillis, M. Beans. Seminar (21st May) entitled "Anti-TRF acceptor site(s) antibody which substitutes for TRF activity in triggering of B lymphocytes."
Harvard Medical School: Discussion with Drs. B. Benaccerraf, B. Goulding, G. Nepom, M. Mescher, R. Germain, K. Ault, S. Schlossman, T. Springer, B. Bevan, A. Nisonoff, R. Finberg, S. Burakoff, M. Dorf, M. Greene, J. Press, and R. Stout. Harvard Medical School Immunology Seminar on May 27 at Amphitheatre D. Seminar at Rosenstiel Research Center of Brandeis University on May 29.
NCI and NIH: Discussion with Drs. G. Shearer, W. Paul, J. Oppenheim, R. Asofsky, E. Shevach, J. Berzofsky, M. Howard, S. Shaw, A. Singer, R. Hodes, D. Longo, D. Sachs, T. Waldmann. Seminar on June 2.
New York University: Discussion with Drs. G. Thorbecke, V. Nussenweig, Z. Ovary, M. Lamm, J. Phillips-Quagliata, R. Basch. Seminar on June 4.

Overall Assessment of the Program

1.	Has the program assisted you in achieving your research objectives? Yes, I have had valuable suggestions about my work through the discussion with the U.S. scientists. I heard that my seminar was also very suggestive and stimulatory to the U.S. scientists.
2.	How can progress in your research effort be enhanced through this program? The most important issues about the molecular analysis of the induction of tumor-specific immunity have been reconfirmed from the discussion with the U.S. Scientists. Moreover, the information exchange was facilitated about the most recent advances in T cell-derived factors which is responsible to govern the cell-cell interactions in the induction of tumor-specific immunity. A contact with the U.S. Scientists will be continued to extend mutual collaborative works.
3.	Please provide information indicating how your efforts have contributed to the progress of the NCI-Japan Cancer Program. As the principal advisors of U.S.-Japan Cancer Research Program, Dr. Hodes and I had discussed about the outline of future directions and plans of the program which may encourage the research of tumor immunology. In my seminar, I discussed about our recent informations for the basic mechanisms of killer T cell induction. This information may provide us with a novel molecular strategy for the future immunotherapy of cancer.

(7) Ichiro Azuma
Institute of Immunological Science, Hokkaido University

Sponsor and Host Institution:
Dr. Ronald B. Herberman, Biological Response Modifiers Program, NCI-Frederick Cancer Research Center
Dates of Visit: March 27th-April 25th, 1982

Summary of Activities:
Object of this study: Recently, various kinds of immunological modalities were applied for the cancer treatment. The object of this study is to visit the researchers and clinicians in the United States and to exchange the informations in this field.
Achievements: From March 27th to April 24th, 1982, I have visited 12 Universities and institutes in 8 cities in the United States. I have presented seminar 4 times and exchanged the informations about recent advance in cancer immunotherapy. The approaches for cancer immunotherapy in the United States are summarized as follows:
1. Nonspecific immunotherapy with immunoadjuvants
Living BCG, MER, MVE-2 and levamisol are used mainly in human lung cancer and malignant melanoma. Cooperative clinical trials concluded that intrapleural injection of living BCG: (McKneally's protocol) was ineffective for the prolongation of survival rate of lung cancer patients (clinical stage I). Synthetic adjuvants, acyl-MDP and retionoid are going to be applied in human cancer.
2. Passive immunotherapy
Significant clinical effect was observed by the bone-marrow transplantation into the patients with leukemia and aplastic anemia from HLA-matched or identical twine donors in Fred-Hutchinson Cancer Research Institute. Transfusion of in-vitro cultured autologous lymphocytes is being tried in NCI.
3. Monoclonal antibody and lymphokine
R. Levy et al. treated B-cell lymphoma patients with monoclonal anti-idiotype antibody. Also they treated T-cell leukemia and cutaneous malignant lymphoma patients with monoclonal antibody directed against a normal differentiation antigen. Irie et al. are preparing "oncofoaetal antigen (OFA)" which was secreted from lymphocyte clones for the treatment of patients with malignant melanoma and sarcoma.
4. Interferon
Cooperative clinical trial is now being carried out for the evaluation of recombinant!!!-interferon in the cancer patients. Phase I study of!!!-type interferon in human cancer has already started.
We have also discussed on the immunological parameters of the cancer patients, the screening systems of immunopotentiators and experimental models of cancer immunotherapy. The collaboration has been planned to evaluate new immunopotentiators developed in both countries.

(8) Kyoichi Kano
M.D. Professor of Microbiology, Department of Microbiology, School of Medicine, State University of New York at Buffalo, Buffalo, New York 14214

Activities during my sabbatical leave in Tokyo from January to the end of June 1981, supported by a National Cancer Institute Fellowship, can be divided into two categories: 1. collaborative research at the host institutions and 2. visits to several institutions to give seminars and lectures to faculty members and students.

1.	Collaborative research at Dept. of Medicine, University of Tokyo, School of Medicine, Tokyo, Japan, and Cancer Institute, Tokyo, Japan.
	a.	Sera of 1 9 patients with infectious mononucleosis (IM) like syndrome and 570 patients with lymphomas or leukemias as well as over 3000 patients with various other diseases were examined for the presence of heterophile antibodies. None of the Japanese patients with IM like syndrome formed heterophile antibodies of Paul-Bunnell (P-B) specificity. On the other hand, sera of 9 of these patients contained heterophile antibodies of Hanganutzin-Deicher (H-D) or Forssman (F) specificities. These findings were in sharp contrast to those observed in Caucasian IM patients who invariably formed P-B antibodies. In studying sera of patients with lymphomas or leukemias, it was found that 24% of these sera contained elevated antibody titers of H-D or F or both specificities. As expected, P-B antibodies were not found in any of these sera. Selected sera were subjected to inhibition tests with purified H-D antigens of bovine erythrocytes. H-D antibodies of these sera were shown to be directed against "high molecular weight glycoprotein" but not against n-glycolyl neuramic acid. For controls, over 3000 sera of patients with various diseases were tested. Only 25 sera contained high titers of heterophile antibodies; they were of H-D or F specificities but not P-B specificity.
	b.	P-B antigens in tissues and sera of Japanese patients with lymphomas and leukemias. Peripheral blood leykocytes of 45 patients with Hodgkin's disease and malignant lymphomas as well as those of 62 patients with various forms of leukemias were subjected to chloroform-methanol extraction followed by DEAE Sephadex colum chromatography. Results of preliminary experiments showed that about 45% of these extracts contained P-B antigens of both BS and B specificities. Attempts to demonstrate P-B antigens in the patient's circulation encountered great difficulties, since hemagglutination inhibition tests had to be employed. As described in la, many of the patients' sera contained rather high titers of H-D or F antibodies. Preabsorption of these sera with sheep or bovine erythrocytes resulted in release of heterophile antigens including P-B antigens into the serum specimens. Thus, many such preabsorbed sera gave false positive results. To overcome the technical difficulties, a method of demonstrating directly P-B antigens in the patients' sera was developed. Group 0 human erythrocytes were treated with tannic acid and glutaconic aldehyde and coated with P-B antibodies which were obtained by an elution procedure. Such antibody coated cells were aggregated upon exposure to corresponding antigens in a solution such as the patients' sera. Because of the time limit of the sabbatical leave, the author had to give up crucial parts of the studies described in lb. It is the author's firm intention to return to the host institution in the near future and complete these studies.

2.	Visits to other institutions to give Seminars and Lectures:
	a.	Fukushima Medical College Jan. 31 - Feb. 4	- a series of 4 lectures on "tumor and transplantation immunology
	b.	Kagawa Medical College Feb. 16	- a seminar on "immune complex diseases"
	c.	University of Kyoto Feb. 20	- a seminar on "immune surveillance"
	d.	Tohoku University Mar. 2	- a seminar on "human tumor immunology, past and present"
	e.	Korean Immunology Society in Seoul May 20	- a lecture on "immune response in human lymphoid malignancies"
	f.	Institute of Medical Science, University of Tokyo June 25	- a seminar on "Autoimmunity"