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A 45-year-old man was admitted after resection of a metastatic brain tumor (papillary adenomatous adenocarcinoma, well differentiated) for both therapy and a search for the primary and any other metastatic lesions. An extensive general examination revealed no evidence of malignant lesion except for fibrous change in the right lung apex by roentgenography and CT scan. Histological examination of the right upper lobe and group II lymph nodes revealed a scar cancer presenting the same histology but no evidence of metastasis. The patient, who received CAP and FVM alternately, is currently healthy with no recurrence after 4 years.

In an attempt to characterize insulitis induced by multiple low doses of streptozocin (SZ), we immunohistochemically examined sequential changes of the subsets of lymphocytes infiltrating the pancreatic islets in CD-1 mice. Daily intraperitoneal injections of 30 mg/kg body wt of SZ for five consecutive days led to lymphocytic infiltration around the islets. Most of the infiltrated cells were initially CD4 positive (helper/inducer) T-lymphocytes and no immunoglobulin-bearing cells were detected. The number of helper/inducer T-lymphocytes increased with progression of the insulitis, then surface immunoglobulin-positive cells (B-lymphocytes) accumulated around the area of CD4 positive T-lymphocytes. CD8 positive (suppressor/cytotoxic) T-lymphocytes were seen scattered throughout the study and only a few asialo GM1 positive (natural killer) cells existed in the area of insulitis. Subsequently, the pancreatic insulin contents were considerably decreased and diabetes occurred on day 21. These observations suggest that CD4 positive T-lymphocyte-dependent B-lymphocyte infiltration in and around islet cells may be associated with islet cell destruction and the development of diabetes in CD-1 mice treated with multiple low doses of streptozocin.

A primary immunodeficiency patient was analysed whose serum IgG and IgE were extremely low but whose IgM and IgA levels were within the normal range or elevated. Southern blot analysis indicated no deletion of structural genes coding for C gamma, C epsilon, or C alpha. The majority of the patient's peripheral B cells expressed IgM and IgD on the surface yet IgG-positive B cells were not detected, suggesting that the defect is in a switch-recombination process from IgM to IgG. The RFLP pattern detected with the S mu and S gamma DNA regions revealed that there was no deletion or large mutation in the switch region DNA. An in vitro IgG production system with pokeweed mitogen showed an abnormality at the transcriptional level and the defects were in both the patient's T and B cells. Addition of recombinant IL-4 (rIL-4) to the normal B cells enhanced IgG production but the patient's B cells did not respond to rIL-4, although the IL-4 receptor was present at the normal level. Messenger RNA and IL-4 protein were not produced in the patient's T cells upon stimulation with phorbol ester and calcium ionophore, whereas IL-2 was normally produced. The patient's lymphocytes showed a proliferative response to various mitogens, including phorbol ester. The transcripts of unrearranged C gamma region genes were not detected in the patient's lymphocytes, suggesting that the chromatin structure of the S gamma region may not be open. These results suggest that the transcriptional defects at the S gamma region gene in B cells and at the IL-4 gene in the T cells may be responsible for the present IgG immunodeficiency. There might be a common transcriptional system operating in a certain step in the activation of both genes.

When multiple low doses (30 mg/kg body wt) of streptozocin were given to CD-1 mice, diabetes associated with L3T4 T-lymphocyte- and B-lymphocyte-predominant insulitis occurred. Thus, a model of type I (insulin-dependent) diabetes was obtained. To treat these diabetic mice, we administered lobenzarit (CCA), a newly synthesized immunomodulator. CCA (2 or 10 mg/kg body wt) significantly inhibited the progression of diabetes by suppressing the severity and incidence of insulitis. Insulin contents of the pancreas were preserved. The possibility that autoimmune-related diabetes can be treated with CCA warrants further attention.

To determine the role of repair of potentially lethal damage (PLD) in the initiation process of neoplastic transformation, Balb/c 3T3 cells treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were temporarily exposed to conditioned medium obtained from density-inhibited Chinese hamster cell cultures, as a post-treatment for the induction of PLD repair. With or without this exposure, cell survival and transformation frequencies were simultaneously determined by colony-formation and focus-formation assays, respectively. Temporary exposure to conditioned medium resulted in a 20-30% increase in cell survival compared with no exposure. Post-treatment with conditioned medium resulted in a 60-65% reduction in transformation frequencies. At the molecular level, the repair of MNNG-induced single-strand breaks of DNA occurred much more rapidly in conditioned medium. These data suggest that PLD repair reduces the in vitro neoplastic transformation through excision repair operative during the cessation of DNA replication. Thus, PLD repair appears to be preventive against neoplastic fixation in initiation of neoplastic development.

In an attempt to clarify the role of cellular immunity in the pathogenesis of acute type B viral hepatitis (AHB, we studied delayed-type hypersensitivity (DTH) skin reaction to hepatitis B surface antigen (HBsAg) and immunohistopathology of livers in patients with AHB. DTH skin reaction to HBsAg developed early in the convalescent phase in all 14 patients with AHB. In contrast, the production of anti-HBs was significantly delayed in these patients, compared with healthy controls immunized with HB vaccine intradermally (P less than 0.001). These observations suggest that DTH to HBsAg but not anti-HBs may be associated with recovery from AHB. In the biopsied livers obtained from patients with AHB, the proliferation of Kupffer cells was extensive and immunohistopathologic studies revealed an accumulation of CD-4 positive lymphocytes in the portal area, a finding which suggested a DTH reaction in the liver with AHB. CD-8 positive cells had infiltrated the lobule and made contact with affected hepatocytes, thereby indicating that a cytotoxic T cell response is involved in damaging of the infected cells. All these observations taken together, we propose that not only a cytotoxic T cell response but also a DTH reaction may be involved in the pathogenesis of AHB.

Cyclosporin A (CYA), when administered to CD-1 mice treated with a subdiabetogenic dose of Streptozocin (STZ), exacerbated the STZ-induced insulitis and elevated the plasma glucose levels, parallel to a reduction of the insulin content of the pancreas. The possible mechanisms of CYA-mediated aggravation of STZ-induced diabetes are discussed.

SISO in doses of 1.0 to 1.8 mg/kg was administered by a 30-minute intravenous infusion every 12 hours to 10 patients with infections, 9 of whom had underlying diseases including malignant diseases, diabetes mellitus, and diabetes insipidus with indwelling FOLEY catheter. The serum concentration of SISO was around 6.75 micrograms/ml in the end of infusion, and less than 1.0 micrograms/ml at 8 to 12 hours after infusion. SISO was given to the patients as a single agent for at least 3 to 5 days and all patients experienced an excellent to good response clinically, and causative organisms which showed a minimal inhibitory concentration of less than 1.56 micrograms/ml disappeared after the treatment associated with clinical improvement. There were no untoward effects noted in this study.