The mechanisms of growth of lymphoma in the lymph node was investigated from the point of view of the interaction between lymphoma cells and lymph node cells by using a transplantable malignant lymphoma (pre-B cell lymphoma) of SJL/J mice. This study indicated that the immunological interaction between lymphoma cells and lymph node cells was important for the growth of lymphoma. For the initiation of this reaction of these cells, the first, Lyt 1⁺2^- cells in the lymph node have to recognize lymphoma cells and stimulate ones. By this interaction, Interleukin-2 and Interferon were produced.
Although it is not clear yet that direct effect of these lymphokines on growth of lymphoma, it was strongly suggested that lymphoma cells could grow in the environment that these lymphokines made because lymphoma had been unable to grow without the existence of this interaction.

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1. It has been suggested that multiple factors are required in CTL induction systems. However, although extensively studied, the exact role of factors, their mechanism of action, and their interrelationships in the pathway inducing generation of CTL are not yet known. IL-2 can potentially function to expand specific T cell clones which have responded to antigen. Therefore, IL-2 may be involved in the amplification of T cell responses. IFNγ may be involved in the induction of IL-2 receptors. Other differentiating factors may be involved that have not yet been biochemically or biologically characterized.
2. We have recently demonstrated that supernatants from mixed leukocyte cultures are able to activate human peripheral blood lymphocytes to cytotoxic effector cells. They are capable of killing allogeneic but not autologous target cells. This cytotoxicity is mediated by T cells possessing receptors for the Fc portion of IgG. Both the precursors of cytotoxic cells and the cytotoxic cell itself in this cytotoxicity system bear Ia-like antigens, The active factors in MLC supernatants which are involved in the generation of these CTL have not yet been biochemically characterized.

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The regulation of antibody production by B cells is governed in large part by the interactions between mutually exclusive T cell subsets with different functional properties, such as T4⁺ helper/inducer and T8⁺ suppressor/cytotoxic subsets. The mere expression of such antigenic markers on T cells, however, dose not necessarily imply the presence of proper functions usually attributed to these subsets. For example, T8⁺ cells lacking Ia-like antigen on their surface from healthy adults did not have any suppressor activity on B cell differentiation in Nocardia water-soluble mitogen (NWSM)-driven coculture system, whereas atypical lymphocytes expressing both T8⁺ and Ia-like antigens, as a probable sign of in vivo activation, in acute infectious mononucleosis exerted active suppression.
In vitro stimulation of T cells with mitogens indicated that Tac antigen appeared in the early stage of G1 phase of the cell cycle and then, Ia-like antigen in the S phase or later. The expression ability of Tac antigen on stimulation might be correlated well with T cell proliferation capability, while the expression of Ia-like antigen might imply some functional activation or differentiation of these T cells.
If the expression of Ia-like antigen on T4⁺ subset was inhibited by the addition of anti-Tac antibody, B cell differentiation in PWM-driven coculture system was markedly impaired. Analysis of functional property of PWM-prestimulated T4⁺ subset in NWSM-driven coculture system indicated that suppressor precursors in T8⁺ subset might be activated to become active suppressors only by their interaction with these PWM-prestimulated T4⁺ cells. The T4⁺, Ia⁺ cells as well as T4⁺, Ia^- cells generated after 8 day-stimulation with PWM exerted a similar help on B cell differentiation in PWM-driven coculture system, while suppressor precursors in T8⁺ subset were activated only after the interaction with T4⁺, Ia⁺ cells, but not with T4⁺, Ia^- cells, indicating these T4⁺, Ia⁺ cells having had a pivotal role for suppressor induction.
These results suggest that the T cell ability to express Ia-like antigen on stimulation might be important for the acquisition of their proper immunoregulatory functions. In this regard, the fact that poor expression of Ia-like antigen on stimulated cord blood T cells was markedly augmented in the presence of high concentrations of human γ-interferon is informative for the ontogenic maturation of T cell functional repertoires.

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NK cell activity was studied in childhood acute leukemia by ⁵¹Cr-release assay using K562 target cells.
NK cell activity of ALL in the remission phase was 23.5±9.2% specific lysis (n=25), being depressed as compared with the normal value of 47.2±5.7% (p<0.01). The decrease of NK cell activity became predominant at the time of onset or relapse: % specific lysis was 9.0±4.9% (n=20). The majority of off-therapy ALL patients still exhibited lower NK cell activity than normal subjects. In vitro studies demonstrated that, among the conventional anti-leukemic agents, prednisolone, arabinosylcytosine and daunorubicine depressed NK cell activity. The anti-leukemic agents appear to contribute to the impaired NK cell activity in ALL. The continuous decrease of NK cell activity even after the cessation of antileukemic therapy, however, cannot be explained by their effect alone, suggesting that the NK cell impairment is one of the characteristic features of ALL.
Serial assays of NK cell activity in five patients demonstrated that a significant decrease of NK cell activity occured 4 to 8 weeks before the relapse when there were no apparent changes of the peripheral blood cell counts and bone marrow pictures. In frank relapse, the NK cell activity was further depressed. These results demonstrated that the assay of the NK cell activity is a useful tool to predict and detect relapse of ALL at an earlier time. The in vitro responsiveness of NK cells to IFN or poly I: C varied according to the stage of the disease.
In remission phase, NK cells responded to both IFN and poly I: C and their activated activity reached the normal endogenous level. NK cells treated with antileukemic agents were also augmented in their activity in response to IFN.

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The induction of cytotoxic cells against autologous leukemia cells were assessed by mixed culture of peripheral lymphocytes in remission stage and preserved autologous leukemia cells added with PHA and IL-2. The results were as follows.
1) Killer cells against autologous leukemia cells were generated in 9 of 10 cases with acute leukemia.
2) Cytotoxic activity was enhanced by the neuraminidase treatment of autologous leukemia cells used as target cell and stimulator cell.
3) Cytotoxic activity in Ia antigen negative cases were lower than in Ia positive cases.
4) Killer cells had cytotoxic activity against autologous and allogeneic leukemia cells, but had no activity to PHA stimulated or non-stimulated autologous lymphocytes.
5) When target cells were treated with Ia antibody, cytotoxic activity against autologous leukemia cells markedly declined, but not changed to allogeneic leukemia cells.
6) Characteristic of killer cells treated with monoclonal antibodies were suggested two population of cytotoxic T lymphocyte with OKT 11⁺, 3⁺, 8⁺, Ia⁺ and NK like cell with Leu 7⁺, OKM 1⁺.

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From peripheral blood of 7 patients with malignant lymphoma and 2 normal donors, large granular lymphocytes (LGL) were isolated and propagated with medium containing interleukin 2. Two to 4 weeks after the beginning of culture, LGL were tested for the cytotoxicity against K562 cells and the patients' lymphoma cells. Although strong cytotoxicity was elicited against K562 target cells, cytotoxicity against lymphoma cells was not elicited except for in a patient with lymphoblastic lymphoma.

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By using two commercial 2-site immunoradiometric kits (SPAC Ferritin kit and RIA-gnost Ferritin kit), changes of normal levels of serum ferritin with aging in male and female were investgated.
The levels well reflected the known changes in iron metabolism during life. The sex difference of ferritin values was found at and over 16 years of age.
In addition to the serum iron, TIBC, transferrin saturation, and complete blood counts, serum ferritin was determined in screening for iron deficiency anemia in junior high school students in Morioka. Serum ferritin assay had advantages over other tests for detection of subclinical iron deficiency. The serum ferritin level less than 15 ng/ml by SPAC or 30 ng/ml by RIA-gnost was indicative of latent iron deficiency. Hb and MCH were the most helpful in the primary screening for iron deficiency anemia. Values below 13 g/dl of Hb and/or 28 pg of MCH were suggestive of iron deficiency anemia.
Additional tests including serum ferritin, serum iron, TIBC, and transferrin saturation are necessary to determine iron deficiency anemia.

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Thiry seven candidates for bone marrow transplantation were given either A) hyperhydration and diuretics (n=26), B) bladder irrigation with A) (n=6), or C) sodium 2-mercaptoethane sulfonate (mesna) with B) (n=5) for the prevention of cyclophosphamide-induced hemorrhagic cystitis. The overall incidence of hemorrhagic cystitis was 42% (11/26) in group A, 33% (2/6) in group B, and 80% (4/5) in group C. Of the patients who developed hemorrhagic cystitis, 5 patients out of 11 in group A and all 6 patients in groups B and C presented early-onset hemorrhagic cystitis. One patient in group C developed both early-and late-onset hemorrhagic cystitis. Symptoms of early-onset hemorrhagic cystitis were mild in most patients in groups B and C, but more severe in patients in group A. Accordingly, late-onset hemorrhagic cystitis mainly occured in patients in group A. Its symptoms were more severe than those of early-onset one. Three patients with late-onset hemorrhagic cystitis were treated with steroids, bladder irrigation or caudal block but without beneficial effects. The symptoms continued until patients died in 6 out of 7.
These data indicate that bladder irrigation as well as administration of mesna appear to decrease the severity of hemorrhagic cystitis, though they may not reduce its incidence induced by cyclophosphamide-conditioning for bone marrow transplantation.

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105 cases of myelomonocytic leukemia (MMoL), including our 10 cases and cases collected from the Japanese literature with hematological findings, were investigated, and the following results were obtained: (1) The classification of acute (AMMoL) and chronic (CMMoL) should be carried out on the basis of the maturity of leukemic cells rather than the survival time. The quantitative criteria for the classification were established in this way. (2) There were about twice as many cases among males than females in both AMMoL and CMMoL. (3) No cases under 30 years of age were found in CMMoL. (4) While there were no cases of gingival swelling, there were some cases of massive splenomegaly or leukopenia in CMMoL. (5) There were few cases of chromosomal abnormality, and some cases of markedly high lysozyme or LDH levels in AMMoL. (6) The median survival from initial symptoms to death and from diagnosis to death were 8.1 and 6.1 months in AMMoL, and 16.2 and 8.4 months in CMMoL, respectively. (7) Blastic crisis in CMMoL was noticed in 50% of the cases. No cases of lymphoblastic crisis were found. (8) 17 cases of prelekemia proceeding to AMMoL or CMMoL were found.

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Adult T cell leukemia virus (ATLV or HTLV) proviral DNA was examined by modified southern blotting method, in peripheral blood mononuclear cells and/or lymph node cells from patients with adult T cell leukemia (ATL) and other various hematological disorders. The presence of ATLV proviral DNA was confirmed in all cases with ATL and some T-cell type with malignant lymphomas. Amount of the provirus DNA correlated remarkably with the clinical picture. However, in ATLV carriers or other hematological patients without ATL who were infected by large amount of multiple blood transfusions, proviral DNA was not detected. The detection of proviral DNA seems to be useful for the diagnosis of ATL in the endemic area and may provide a powerful tool for the classification of T cell malignancies.

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The results of immunosuppression or androgen therapy for aplastic anemia in 23 institutions in Japan were analyzed. The in vitro test for the detection of suppressor cells in peripheral blood of the patients, and the effect of fluoxymesterone on the erythroid colony formation of bone marrow cells of the patients were also examined. The immunosuppression therapy includes the menthylprednisolone pulse therapy, antilymphocyte globulin administration, and oral administration of prednisolone or cyclophosphamide.
Immunosuppression therapy was effective in 37.5% of 72 cases of aplastic anemia on the whole. There was no correlation between the clinical response to the immunosuppression therapy and the suppressive activity of mononuclear cells in vitro. Antilymphocyte globulin was effective in 35.3% of 17 cases of severe aplastic anemia, but there were no patients who had recovered to the normal hematological values.
Androgens were clinically effective in 64% of 50 cases of aplastic anemia. There was no correlation, however, between the clinical response to androgens and the in vitro responsiveness of bone marrow cells to fluoxymesterone.

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A case of T-ALL with suppressor activity was reported. A 29-year-old man with a giant thymoma, remarkable leukocytosis and hypogammaglobulinemia was diagnosed acute T lymphoblastic leukemia, based on the hematological and immunological examinations. The leukemic blasts with high N/C ratio were positive for E-rosette formation, but were negative for IgG-FCR, Ia-like antigen, SmIg, TdT reaction and anti-ATLA antibodies. Furthermore, 71% and 58% of these blasts were reactive to OKT 8 and 10, respectively, showing them to be in the level of mature thymocyte.
In vitro studies showed suppressor activity of these blasts specifically on IgG synthesis by normal peripheral lymphocytes.
Clinically, the patient's hypogammaglobulinemia returned to normal level after radiochemotherapy, suggestig the suppressor activity of these blasts in vivo.

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An unusual case of primary myelofibrosis which revealed clinical findings similar to CML is described. A 53-year old man was admitted in Feb. 1980 because of general fatigue and splenomegaly. Peripheral blood analysis revealed leukoerythroblastic anemia with tear drop cells and giant platelets. On bone marrow biopsy, an increase in collagen fibers and thickening of bone trabeculae were observed. Ferrokinetic study showed extramedullary hematopoiesis and ineffective hematopoiesis in the liver and the spleen. He was diagnosed as primary myelofibrosis but decrease of neutrophil alkaline phosphatase score and basophilia were suggestive of CML. In April 1980, clinical findings similar to a blastic phase of CML occurred and were improved with administration of aclacinomycin-A and prednisolone. In Dec. 1980, cardiac tamponade due to massive pericardial effusion developed, which was bloody and contained atypical myeloblastoid cells. Cardiac tamponade was improved by repeated puncture. General condition was fairly well by the administration of prednisolone until his death in June 1981 because of renal failure. It was suggested that cardiac tamponade could have resulted from the infiltration to pericardium or myocardium of atypical myeloblastoid cells.

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A 32-year-old woman with idiopathic autoimmune hemolytic anemia (IAIHA) was admitted to our hospital in July 1980 because of severe headache and tinnitus. She had been treated with prednisolone until four months before admission. On admission an acute exacerbation of IAIHA was suggested from severe anemia with reticulocytosis, increase in serum indirect bilirubin and lactic dehydrogenase, undetectable haptoglobin and positive Coombs' tests. In addition, marked papilledemas on bilateral ocular fundi were observed. CSF findings were normal except for elevation of the pressure. Other neurological examinations and brain CT scanning showed no abnormalities. These findings indicated benign intracranial hypertension (BIH). Administration of prednisolone resulted in remarkable improvement of both anemia and BIH within three months. Thereafter for three years IAIHA has been in remission and BIH has revealed no recurrence. It is suggested that BIH in the patient might have been caused mainly by withdrawal of steroid and acute exacerbation of IAIHA.

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A thirty-five years old woman of severe aplastic anemia was treated by allogeneic bone marrow transplantation after removal of hemagglutinin in application of immunoadsorbent column for compromizing major ABO incompatibility (A→O). Transfusion of 1,300 ml of whole blood obtained by bone marrow aspirate, did not cause significant hemolytic reaction. Subsequent rise of hemagglutinin titer occurred 8 days after transplantation, but hemolysis did not occur, and hemagglutinin decreased spontaneously thereafter.
The patient died of pneumonia 18 days after transplantation without the hematological reconstitution.

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