SUMMARY REPORTS OF EXCHANGE SCIENTISTS

(1) Naoyoshi Mori
Basic Medical Sciences, University of Tsukuba

Sponsor and Host Institution:
St. Jude Children's Research Hospital
Dates of Visit:
From December 1, 1981 to January 2, 1982 at University of Southern California in Los Angeles. From January 3, 1982 to February 15, at St. Jude Children's Research Hospital in Memphis. From February 16, to February 18 at City of Hope Medical Center in Duarte. From February 21 to February 26 at University of Washington in Seattle.

Summary of Activities:
Lightmicroscopically I examined 400 cases of the malignant lymphomas and related disorders at University of Southern California and 500 cases at St. Jude Children's Research Hospital. The results obtained were as follows.
1. In these institutions, B lymphomas were predominant and most common type of them was follicular lymphoma. Among the diffuse lymphomas, large cell type was predominant, whereas medium-sized cell type was less common. Besides these characteristics, non-hodgkin lymphomas of the U.S. showed the following characteristics.
1) They occasionally showed focal involvement in the lymph node, sparing the sub-capsular area.
2) The lymph node involved not infrequently had extensive fibrosis.
3) In the cases of the diffuse, large cell lymphomas, the neoplastic cells demonstrated variation in size, occasionally exhibiting bizarre giant cells. From these facts, I understood that host responses of U.S. patients were quite different from those of Japan.
2. I examined the cases diagnosed as necrotizing lymphadenitis or granulomatous lymphadenitis at the University of Southern California and St. Jude Children's Hospital. Most of these cases were chronic lymphadenitis with epithelioid cell reaction, but in each institution, two cases which fit the diagnosis of necrotizing lymphadenitis proposed by the Japanese researchers were observed. But the necrotic foci of these cases tended to be more widespread compared with that of Japanese cases and some of them occupied almost all the parenchyma of the lymph node. On the other hand, the immunoblastic reaction around the necrotic foci was not so prominent as the Japanese cases.
3. There was not any case which fitted the diagnosis of systemic lymphadenopathy simulating Castleman's lymphoma. In our institution of Tsukuba University, we already experienced 13 cases including those from the other institutions. So, this can be considered to be fairly specific disorder of Japan.
4. Although we couldn't investigate hairy cell leukemia because it was a rare disorder in Japan, many cases of hairy cell leukemia were kept viable in liquid nitrogen at University of Washington. So I brought back the smears of 2 cases of hairy cell leukemia to Japan.
Upon investigation with electron immunoperoxidase, the neoplastic cells of one case showed positive reaction with anti-IgM antiserum. So, it can be concluded that some of the hairy cell leukemia are the neoplasm of B lymphocytes. They will send us more cases of hairy cell leukemia, so we will continue our collaboration.

Specification
1. The program assisted in achieving my research objectives, because I understood marked differences of the histology, incidence and type of the malignant lymphomas and related disorders between U.S. and Japan. This means that we need to pay more efforts to exchange scientific information with researchers in the U.S. and at the same time, we have to establish the classification based on the actual state of the malignant lymphomas in Japan.
2. As I mentioned above, the collaborative work with pathologists of the University of Washington concerning the investigation of cytoplasic immunoglobulin of hairy cell leukemia was quite effective and it will be continued.
3. I exchanged informations on various immunological techniques including electron immunoperoxidase and the immunohistological staining using monoclonal antibodies. This was quite helpful to me and the U.S. researchers, knowing new techniques or knowing how to carry out difficult points on these techniques. I also introduced the special cases such as necrotizing lymphadenitis or Castlman like lymphadenitis in Japan and learned many interesting cases such as hairy cell leukemia, prolymphocytic leukemia or signet ring cell lymphoma in the U.S. And these kinds of information helped us greatly.



(2) Kohji Ezaki, M.D.
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research

Sponsor and Host Institution:
Fritz H. Bach, M.D.
Immunobiology Research Center, University of Minnesota
Dates of Visit: Feb. 21-March 22, 1982

Summary of Activities:
In vitro generation of anti-tumor cytotoxic lymphocytes by auto- and allosensitization is useful method to assess the specific immune reaction and will be an in vitro model of tumor immunotherapy. With this Program, I planned to learn 1) the ideas of in vitro sensitization, 2) characterization of cytotoxic cells generated in in vitro sensitization, 3) possibility of expansion of these cytotoxic cells and future use for tumor immunotherapy.
Initially I intended to generate cytotoxic cells by using mitomycin (MMC) treated autologous tumor cells alone as stimulator, but the lymphocyte response to autologous tumor cells were weak and in vitro generation of cytotoxic cells was usually negative. In Dr. Bach's lab, three different approaches were taken for generating cytotoxic lymphocytes capable of lysing autologous tumor cells. Firstly, MMC treated allogeneic normal lymphocytes were added to a mixture of patient's lymphocytes and MMC treated autologous tumor cells. Secondly, since lymphoblastoid cell lines and human leukemia cells often express cross-reactive serologically detectable antigens, lymphocytes were sensitized to MMC treated autologous lymphoblastoid cell lines (LCL). Thirdly, lymphocytes were sensitized to MMC treated allogeneic cells pooled from 20 normal individuals, since such 'pool' sensitized lymphocytes lyse virtually all allogeneic cells.
These methods induced generation of cytotoxic cells capable of lysing autologous tumor cells. However, these cells were also cytotoxic against allogeneic LCL cells and K562 culture cell lines, which indicate that both cytotoxic T cells and NK like cells were generated in in vitro sensitization. The best way to determine whether lysis of autologous tumor cells is mediated by cytotoxic T cells or NK like cells, is to use monoclonal antibody. The treatment of stimulated cells with monoclonal anti-human T cells antibodies, OKT3 and OKT8, and complement, diminishes cytotoxic T cell activity against autologous tumor cells, but does not decrease lysis of K562 cells. These findings provide the evidence that lysis of autologous tumor cells is mediated by cytotoxic T cells rather than NK Iike cells.
Next step will be the cloning of these cytotoxic cells and then the expansion of these cells by using T cell growth factor (TCGF). Once we get enough lymphocytes cytotoxic to autologous tumor cells, these cells will be applied for adoptive immunotherapy of malignant diseases.
I now know that the generation of cytotoxic T cells against autologous tumor cells can be induced by various stimulators. I would like to evaluate the most useful way for the generation of the cytotoxic cells and also the effect of interferon or other Biologic Response Modifiers (BRM) for generation. This technique may be helpful for in vitro evaluation of BRM.
I would like to continue and extend this kind of study in collaboration with Dr. Bach who has done pioneering work in this field.