BALB/c mice neonatally inoculated with semiallogenic lymphoid cells develope host-versus-graft disease (HVGD) with typical immunological features of human SLE. These mice showed high level of serum IgG₁ and IgE, and these evidence may reflect the role of IL4.
Neonatal treatment of HVGD mice with anti-IL4 monoclonal antibody restored the disease, i.e. normal serum IgG₁ and IgE level and no histopathological changes in the liver. Although anti-IL4 treatment at older age failed to show inhibitory effect on HVGD. These evidence strongly indicate that IL4 play an important role for HVGD at initial phase.
6 out of 140 HVGD mice developed malignant lymphoma. All of them were host origin. We established two cell lines which grew both in vivo and in vitro (KTY101, 102). Electronmicroscopically, numerous type C retrovirus were seen and occasionally typical figures of budding were observed. These type-C retrovirus may be concerned with the lymphomagenesis and autoimmune phenomena in HVGD mice.
By northern blot analysis or RT-PCR analysis, IL2 mRNA was found in KTY101 and IL4 mRNA in KTY102. These lymphokine production by the lymphoma cell lines may reflect the unbalance of cytokine production under HVGD.

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Myeloma cells produce IL-6 constitutively, and express its receptor on their surfaces. In vitro, exogenously added IL-6 promotes the growth of myeloma cells from about half of the patients. Therefore, IL-6 is considered as an autocrine growth factor for some myeloma cells. Plasma cells obtained from bone marrow aspirates of benign monoclonal gammopathy (BMG) cases produced IL-6 transiently only after IL-1 stimulation, but not constitutively. Therefore, constitutive production of IL-6 is considered to be characteristic of transformed plasma cells and involved in pathogenesis of multiple myeloma. In two cases with cytokine producig tumors, IL-6 producing renal cell carcinoma and IL-1 producing lung cancer, we could confirm the biological activities of IL-1 and IL-6 on myeloma cells and plasma cells in vivo. To understand the mechanism of the constitutive expression of IL-6 gene in myeloma cells, first, we performed Southern blotting analysis, but we found no gross structural abnormality of the IL-6 gene in myeloma cells. Second, we studied NF-IL6 mRNA expression in myeloma cells by RT-PCR method; NF-IL6 is a nuclear factor that specifically bind the promoter region of the IL-6 gene and activate its transcription. NF-IL6 mRNA expression was detected in a human myeloma cell line, KMS-5 and freshly isolated myeloma cells. Therefore, NF-IL6 may be involved in constitutive IL-6 production in myeloma cells.

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Recent studies have suggested that some cytokines are involved in the growth of lymphoid neoplasma. We studied the production of cytokines in 28 patients with T-cell lymphoma using the northern blotting analysis and the immunohistochemical technique.
Of 28 cases of T-cell lymphoma, IL-4 was detected in 9 cases and IFN-γ was detected in 8 cases. IL-3, TNFα and GM-CSF were detected in 1, 1 and 2 cases, respectively. With regard to histologic subtype of 8 cases which expressed IL-4, 2 cases were angioimmunoblastic lymphadenopathy type and 3 cases were angiocentric lymphoma in sinonasal region, which showed the characteristic histology.
All 8 cases expressing IL-4 showed increased immunoglobulin in sera. Since IL-4 has a variety of biological activities for not only B-cells but also T-cells, these results indicate that IL-4 may play an important role in the histopathogenesis and the growth of T-cell lymphoma.
In the cases which expressed IFN-γ, T-zone histocytes and/or the clusters of epithelioid cells were seen more frequently. It suggests that IFNγ may be involved in the formation of Lennert's lesion.

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PTHrP has been shown to be the main causative factor of humoral hypercalcemia in ATL. It is consitutively over-expressed by ATL tumor cells in vivo. PTHrP gene expression in vivo was shown to be induced by HTLV-1 infection before malignant transformation of the infected cells. Molecular mechanism of induction of this gene expression was investigated by CAT assay with cotransfection of HTLV-1p40^tax expression plasmid and various construct of PTHrPCAT plasmid. Our results indicate that PTHrP promotor is trans-activated by p40^tax, and the responsive element of this transactivation reside within 624bp upstream of transcription start site of exon lb. It is also suggested that zinc finger transcription factor(s) may participate in the transactivation of PTHrP gene expression.

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To evaluate the clinical effect by administration of recombinant human granulocyte-stimulating factor (rhG-CS) post chemotherapy in non-Hodgkin malignant lymphoma (NHL), fifteen patients with NHL were subjected to this study. In patients with CHOP, VEPA or M-FEPA combination chemotherapy, administration of rhG-CSF ameliorated the decrease in absolute neutrophil count after the cytotoxic chemotherapy and was effective for reducing infection complications associated with neutropenia. These clinical effects were observed in ProMACE/CytaBOM regimen as the third generation chemotherapy. Furthermore, administration of rhG-CSF post cytotoxic chemotherapy increased peripheral hematopoietic progenitor cells, thus suggesting promising therapeutic potential for harvest for autografting.
No adverse effects were observed except for one patient complaining of a bone pain of mild degree. rhG-CSF showed no effect on platelet glycoprotein expression and aggregation.
Recently, it has been reported that blood neutrophils may synthesize mRNA and proteins important in inflamation including variuos cytokines such as interleukin-1 (IL-1), interferone-alpha (IFN-α) and tumor necrosis factor-α (TNF-α). Administration of rhG-CSF provided no fluctuation of serum IFN-α level except for one case with peripheral T-cell lymphoma expressing IFN-transcript in peripheral neutrophils prior G-CSF treatment. Slight elevations of serum TNF-α level associated with rhG-CSF treatment in two patient, although the present study showed no evidence that their neutrophilsproduced TNF-α. These results suggested that further study will be needed to clarify in vivo significance of G-CSF in the cytokine network system.
Finally, we studied on anti-tumor effect of administration of rhG-CSF in CDF1 mice inoculated with L5178Y-ML25 lymphoma cells. Administration of rhG-CSF inhibited the liver metastasis and prolonged the overall survival, thus suggesting the hyposis that the use of rhG-CSF in some patients with NHL might control the disease with activation of netrophils.

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Fourteen adult patients with resistant malignant tumors (3 with malignant lymphoma, 3 with acute lymphocytic leukemia, 5 with recurrent breast cancer and 3 with germ cell tumor) received high dose chemotherapy followed by autologous bone marrow transplantation (ABMT) and daily infusion of granulocyte colony stimulating factor (G-CSF). All the 14 patients showed bone marrow engraftment. Median neutrophilic recovery over 500/cmm was 12 days after ABMT, and no life-threatening infection occurred during neutropenic period. As compared with literature controls of high dose chemotherapy followed by ABMT not using G-CSF in Western countries, our results showed earlier recovery of neutrophils. It is suggested that G-CSF may shorten neutropenic period after ABMT. Non-hematologic regimen-related toxicities were under control. No therapy-related death was observed. Disease oriented, multicenter phase II studies of high dose chemotherapy followed by ABMT and daily infusion of G-CSF are ongoing.

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I reported three dimensional karyometric study on the nuclei of lymphoma cells of non-Hodgkin's lymphomas by computerized reconstructed models made from completely serial semi-thin sections cut from Epon embedded specimens.
Cases examined were 11 cases, composed of 8 of B-cell lymphoma; 1 diffuse lymphoma (DL) of small cell type, 2 DL of medium-sized cell type, 1 DL of mixed type, 2 DL of large cell and 2 follicular lymphoma of medium-sized cell type, and 3 of T-cell lymphoma; 1 DL of large cell type and 2 adult T cell leukemia/lymphoma. The tonsils were examined for the comparison as normal component cells.
Cleaved nuclei of B-cell lymphomas showed undulations on the nuclear surface resembling cerebral sulci. Convoluted nuclei of T-cell lymphomas showed rough consecutive curvature as twisted short sticks with mild surface irregularity. Three dimensional shape coefficient of surface irregularity revealed that cleaved nuclei of B cells were more irregular than convoluted unclei of T cells. These results were different from those of previous reports concerning nuclear shapes by a usual two dimensional observation that convoluted nuclei seems to be more irregular than cleaved nuclei.
The discrepancy between results of the present study and those of previous reports by usual light microscopic observations seemed to owe to not only the difference of thickness of preparation, but resolving power on different orders. Because thin section revealed more detailed nuclear shape than thick sections.

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A comparative study between three dimensional nuclear morphology using computerized karyometric method and immunohistochemical characteristics by avidin-biotin complex technique was performed to clarify the histogenesis of B cell lymphomas. A total of 15 cases consisted of 2 of diffuse lymphoma, small cell type (DL-small), 4 of follicular lymphoma, medium-sized (FL-medium), and 9 of diffuse lymphoma, medium-sized (DL-medium). Non-neoplastic tonsils were also used as control.
From the results of three dimensional karyometric and immunohistochemical analysis, 15 cases were divided into three groups:
Group I (2 cases of DL-small and 4 cases of DL-medium): This group has almost spherical unclei similar to those of mantle zone lymphocytes (MZLs), and is immunohistochemically considered to be of MZL origin.
Group II (2 cases of FL-medium and 4 cases of DL-medium): This group has cleaved nuclei similar to those of follicular center cells (FCCs), one case of FL-medium is immunohistochemically recognized to be of FCC origin, other cases are considered to be of MZL origin,
Group III (2 cases of FL-medium and 1 case of DL-medium): This group has intermediate nuclei between MZLs and FCCs, and the cellular origin is immunohistochemically undetermined.
These findings suggest the followings:
(1) Most small cell and medium-sized cell lymphomas possessing spherical nuclei may be of MZL origin.
(2) Medium-sized cell lymphomas possessing cleaved nuclei may be not always of FCC origin, and some may be of MZL origin.

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Malignant lymphoma originating from the uterus is reported extremely rarely. Since Epperson described the first case in 1950, no more than about fifty cases have been reported world wide. Here we report two cases of primary uterine malignant lymphoma diagnosed according to Fox and More's criteria. One of the patients was a 39-year-old housewife who suffered from atypical genital bleeding. Hysterectomy was performed and histological examination revealed malignant lymphoma, diffuse, medium sized. Upon immunohistochemical examination, the tumor cells were positive for several antibodies against B lymphocytes and also for CD74 (LN2). The patient is currently alive and well after surgery. The other patient was an 80-year-old housewife who suffered from abdominal discomfort. Clinical examination revealed abnormal enlargement of the uterus and obstruction of the urinary tract. Eight days after admission, she died of general consumption, and autopsy was performed. The uterus was markedly enlarged with a tumor, which extended to the serosa of the intestine and the peritoneum, involving one lymph node. However, there were no other tumors in other organs examined. Histologically, the tumor cells were distributed diffusely throughout the entire uterine wall and were medium-sized lymphoid cells. Immunohistochemical analysis revealed a B-lymphocyte nature, with positivity for L26, CD20, CD22, CD74 (LN2) and sIgD (surface IgD), but both T lymphocytic and histiocytic markers were negative.

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174 peripheral T-cell lymphomas, classified according to the updated Kiel classification (Suchi), were immunophenotypically studied with a panel of monoclonal antibodies reactive with T-cell differentiation antigens in cryostat section and/or cell suspension. By immunologic studies, 50% of the lymphomas were of helper/inducer (CD4) phenotype, 6% were of cytotoxic/suppressor (CD8) phenotype, 3% expressed both CD4 and CD8, 3% lacked both CD4 and CD8, and 36% were phenotypically undetermined because of an admixture of almost equal number of CD4- and CD8-positive cells. The phenotypically undetermined cases were more frequently noted in low grade lymphomas than in high grade tumors, and the latter often showed the loss of pan-T antigens, although there was no definite correlation between histologic category and immunophenotype. CD25, strongly detectable in anti-HTLV-1 antibody-positive cases, was negative or weakly expressed in anti-HTLV-1 antibody-negative cases. Anaplastic large cell lymphomas (LC-Ana) strongly expressed CD30, which was sometimes detectable in only blast-like cells of low grade tumors. 71% of the lymphomas expressed Ia antigens. In this series, the clinical data were available for 154 patients. For individual markers, the expression of CD30 and/or HLA-DR was associated with a longer actuarial survival (p<0.05 by the generalized Wilcoxon test), but, in the population excluding LC-Ana, the significant difference was undetectable between the groups with and without CD30. Further, the absence of CD25 or presence of CD3 and/or CD7 on tumor cells correlated with a relatively favorable prognosis, but not significantly. The detection of CD4 and/or CD8 had relatively little prognostic value.

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