Biomedical subjects
Publications and source records attributed to K Okuno.
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Preoperative intra-arterial infusion neo-adjuvant chemotherapy, in combination with local vein blocking, was administered to thirty-one patients with locally advanced stage III breast cancer. The anti-cancer drugs and dosages used were 500 mg of 5-Fluorouracil (5FU), which was infused daily for 7-14 days, and 20 mg of Adriamycin (ADM), which was administered as a bolus dose twice into the subclavian and internal mammary arteries. The response rate of this method on the primary tumor was 48.4 per cent, and, histologically it was found to be as high as 90.3 per cent. The response rate of the clinical effects on the regional lymph nodes was 50.0 per cent, however, histologically, it was found to be lower than that of the primary tumor. In the long-term follow-up study the 5-year survival rate was 72.2 per cent. Thus, this method seems to be effective as a combined modality in cases of locally advanced stage III breast cancer.
An adoptive therapy model has been utilized to examine the requirements for T cells to promote eradication of a disseminated, retrovirus-induced, syngeneic leukemia. Complete tumor elimination required that the transferred T cells proliferate in the host and mediate an anti-tumor effect for more than 30 days. Non-cytolytic L3T4+ T helper (Th) cells were capable of eliminating disseminated tumor without the participation of Lyt-2+ cytotoxic T cells (Tc). Purified or cloned Lyt-2+ T cells were also effective in therapy, but required the concurrent administration of either L3T4+ Th or interleukin 2 (IL-2) for optimal efficacy. L3T4+ Th appear to function via secretion of lymphokines that activate macrophages to a cytotoxic state. Lyt-2+ Tc, in addition to direct cytotoxicity, may mediate tumor eradication in part by secretion of lymphokines that activate in vivo tumoricidal macrophages. These studies suggested that the reported efficacy of individual T cell subsets in therapy of particular tumors might not reflect resistance or susceptibility to a cytotoxic effector mechanism, but rather the efficiency with which a T cell subset is activated by the tumor and/or recognizes the tumor antigen. Methods were developed to independently assess the activation and proliferation requirements of each subset. L3T4+ Th required that macrophages degrade tumor antigens in lysosomes and present the antigens in the context of class II molecules, and produced IL-2 and IL-4 as endogenous growth factors. By contrast, Lyt-2+ T cells recognized the tumor directly, required macrophages only to produce IL-1 for activation, and produced IL-2 but not IL-4 as an endogenous growth factor. The ability of T cell subsets to recognize the distinct retroviral tumor antigens expressed on FBL leukemia was assessed using cell lines or recombinant vaccinia viruses transfected with selected retroviral genes. Highly selective antigen recognition was detected, with Lyt-2+ Tc cells recognizing products of gag but not envelope genes, and L3T4+ Th recognizing envelope but not gag products. The results suggest that even complex unique tumor antigens may elicit only limited host T cell responses.
The effect of interleukin-2 (IL-2), injected directly into the tumor-bearer's spleen, on inhibition of tumor metastasis was evaluated. C3H/HeN mice were inoculated intradermally with 2 X 10(6) X5563 syngeneic tumor cells on day 0, and the tumor was surgically resected on day 10. The operation failed to prevent tumor death of these mice within 3 weeks. Autopsy of these mice revealed that death was due to systemic metastasis of tumor cells to lymphoid organs including the liver although the tumors had been successfully removed without any visible local recurrence. In this model, we administered IL-2 by intrasplenic injection daily for 3 days after operation. Mice treated with an intrasplenic injection of IL-2 showed a significantly prolonged survival time. Histological findings after this treatment revealed lymphoid cell proliferation of the spleen, no metastatic foci were found in the liver. Lymphokine-activated killer (LAK) activity from IL-2 injected spleen was also augmented. Intravenous (i.v.) and subcutaneous (s.c.) administration of IL-2 were not effective. A major difficulty in achieving significant immunologic effect in vivo by IL-2 infusion is the relatively short half-life of IL-2. Therefore IL-2 administered directly into the responding lymphoid organ is theoretically reasonable. In fact, treatment with intrasplenic injection of IL-2 significantly augmented the antitumor activity. Splenic arterial infusion of IL-2 may be an appropriate route of administration for adjuvant immunotherapy in human cancer.
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Nonspecific tumoricidal effectors, called lymphokine-activated killer (LAK) cells, can be induced from the tumor-bearer's spleen in vitro. The adoptive transfer of such LAK cells to a patient with unresectable hepatoma was performed in this study. About 2.4 X 10(9) LAK cells generated from the autologous spleen were adoptively transferred to the patient via hepatic arterial catheter. Signs of toxicity encountered with LAK cell infusions comprised chills and fever only. Chemical studies of hepatic, renal, and hematologic parameters were normal; pulmonary function studies revealed no changes after infusion. With the transfer of LAK cells, serum alpha-fetoprotein (AFP) levels were markedly decreased and ascitic fluid retention was transiently reduced. Though the therapeutic effect was transient, these trials offered hope for a new therapeutic approach to unresectable hepatoma. Further, the availability of large amounts of recombinant interleukin-2 (rIL-2) may now make widespread use of this approach possible.
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The requirement for signals in the induction of cytotoxic T lymphocytes (CTL) from thymocyte precursors has been investigated. Either unfractionated or peanut agglutinin-binding (PNA+) C3H/He thymocytes were stimulated with mitomycin C(MMC)-treated, 2,4,6-trinitrophenyl(TNP)-modified syngeneic spleen cells in the presence of a variety of lymphokine preparations. Cellfree supernatant (CFS) from purified protein derivatives(PPD-CFS) stimulated Mycobacterium tuberculosis (Tbc)-primed cells, or partially purified interleukin 2 (IL 2) mediated strong cytotoxic responses in unfractionated thymocytes, whereas only PPD-CFS at final concentrations beyond 30% was active for CTL generation in PNA+ thymocytes. Neither IL 2 at concentrations of below 60 U/ml nor a low concentration of PPD-CFS (at final below 10%) had such a capacity. The addition of monoclonal anti-IL 2 receptor antibody completely blocked CTL generation induced by PPD-CFS in PNA+ thymocytes. In contrast, anti-immune interferon (IFN-gamma) antibody showed a marginal effect. PPD-CFS (10%) and IL 2 (10 U/ml) could synergistically trigger PNA+ thymocytes to induce CTL generation. These results suggested that both IL 2 and "helper" factors other than IL 2 are required for CTL generation from PNA+ thymocytes. We refer to these kinds of helper factors as killer helper factors (KHF). Partially purified IL 2-free KHF show two peaks of activities at apparent m.w. 14,000 to 34,000 and 44,000 to 90,000, and are heterogeneous with respect to isoelectric point, which is between 4.5 and 5.1. Cultures that received TNP-modified syngeneic cells and KHF on day 0 and IL 2 on day 2 generated potent CTL responses, whereas the addition of IL 2 on day 0 followed by the addition of KHF on day 2 to the culture was ineffective, suggesting that KHF is required in the early phase of the culture to achieve optimal CTL responses.
The roles of killer-helper factor (KHF) and accessory cells bearing I-region associated antigen (Ia) in the generation of cytotoxic T lymphocytes (CTL) were analyzed. Peanut agglutinin-binding (PNA+) thymocytes from C3H/HeN mice generated efficient CTL responses against 2,4,6-trinitrophenyl (TNP)-modified syngeneic spleen cells in the presence of cell-free supernatant (CFS) derived from purified protein derivatives (PPD)-stimulated Mycobacterium tuberculosis-primed BALB/c spleen cell culture (PPD-CFS). The KHF which is present in PPD-CFS devoid of the activities of IL-1 or IL-2 was required in conjunction with IL-2 for generation of CTL in PNA+ thymocytes. In contrast, PNA- thymocytes as well as spleen cells could generate CTL in the absence of helper factors. However, a significant CTL response against Ia-negative syngeneic tumor cells was not induced from either PNA+, PNA- thymocytes or spleen cells in the absence of Ia-positive accessory cells. Moreover, the treatment of spleen cells with relevant anti-Ia antiserum plus complement before TNP-modification abrogated the stimulatory capacity of TNP-spleen cells. In both cases, the addition of Ia-positive accessory cells restored the impaired capacity of TNP-modified stimulator cells. The addition of IL-1 to the culture of PNA- thymocytes or spleen cells stimulated with TNP-X5563 cells in the absence of accessory cells restored the CTL generation. In contrast, the addition of IL-1 to the culture of PNA+ thymocytes was ineffective. The role of Ia-positive accessory cells in the generation of CTL in a subpopulation of thymocytes is discussed.
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GOT and GPT activities were measured in percutaneous needle biopsy specimens of human liver tissue from 98 cases including normal subjects and patients with various liver diseases. Hepatic GOT activity was markedly decreased in liver tissue of patients with nonalcoholic liver cirrhosis. Hepatic GPT activity was markedly decreased in liver tissue of patients with alcoholic liver cirrhosis. The GOT/GPT ratio in liver tissue was increased in patients with alcoholic liver cirrhosis (5.32 +/- 2.03) and alcoholic liver disease (4.78 +/- 2.43). The increased SGOT/SGPT ratio in patients with alcoholic liver disease is due to primarily to the increased LGOT/LGPT ratio.
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A patient with the Marfan syndrome and echocardiographic and angiocardiographic evidence of hypertrophic cardiomyopathy is presented. Endomyocardial biopsy was performed. Histologic abnormalities of the endomyocardium noted in this patient were considered to be related to the basic generalized connective tissue abnormality, and the patient subsequently developed myocardial disease compatible with hypertrophic non-obstructive cardiomyopathy. We believe that this case emphasizes the possible co-existence of subclinical myocardial disease in patients with the Marfan syndrome.
The present study deals with the effect of in vivo administration of interleukin 1 (IL 1) on the induction of tumor-specific immunity. Culture fluid supernatant (CFS) containing IL 1 was obtained by stimulating J774.1 cells with lipopolysaccharide. C3H/HeN mice were inoculated intradermally with viable syngeneic X5563 tumor cells, followed by five consecutive subcutaneous or intraperitoneal inoculations of IL 1-containing CFS. Lymph node and spleen cells from IL 1-CFS-treated or -untreated C3H/HeN mice 8 days after the tumor inoculation were tested for 1) cytotoxic T lymphocyte (CTL) responses as measured by subsequent in vitro sensitization with X5563 cells, 2) delayed-type hypersensitivity (DTH) responses as measured by utilizing a local adoptive transfer, and 3) tumor-neutralizing activity in a Winn assay. Lymph node cells or spleen cells from IL 1-CFS-treated X5563 tumor-bearing mice not only exhibited enhanced CTL and DTH responses, but also produced complete tumor neutralization, in contrast with cells from IL 1-CFS-untreated X5563 tumor-bearing mice. In vivo protective immunity augmented by IL 1-CFS was tumor-specific and Lyt-1+2- T cell-mediated. The molecules responsible for enhanced induction of tumor-specific immunity co-migrated with IL 1 activity on gel filtration. These results indicate that IL 1 has the potential to augment tumor-specific Lyt-1+2- T cell-mediated in vivo protective immunity in tumor-bearing hosts.
A comparative study of rat and human mammary tumors was undertaken to clarify the mechanism of hormone dependency by the PAP method. In normal mammary glands, histological estrogen receptor ER (+) cells were observed in the ductal epithelium and acinal cells, while only ER (-) cells were noted in HAN. After overiectomy, 55.6% of the ER (+) cells changes to ER (-). Furthermore, histological changes were glandular atrophy, anaplastic changes, (with) the remaining ER (+) cells (being in the) insular group. Those ER (+) cancer cells seem to be different in hormone sensitivity. As for human mammary glands, proliferation of ER (+) cells was observed in papillary lesions as duct papillomatosis. In the cancer tissues as a whole, ER (+) and ER (-) cancer cells were mixed, showing a so-called mosaic pattern.
In vitro activation of peritoneal macrophages by Propionibacterium acnes and its immunotherapeutic potential for inhibiting metastasis was investigated. C3H/HeN mouse adherent peritoneal exudate cells as a source of macrophages were treated in vitro with P. acnes. These P. acnes-activated macrophages were tested for tumoricidal activity in vitro and antimetastatic activity in vivo. In vitro cytotoxicity tests revealed that they had potent cytotoxicity. Surgical resection of X5563 tumors in syngeneic C3H/HeN mice 10 days after the tumor implantation failed to rescue the hosts from tumor metastasis despite successful removal of the primary tumor. When the activated macrophages were transferred intravenously into C3H/HeN mice following the surgical operation, an appreciable number of mice survived without exhibiting any sign of metastasis. Thus, these results demonstrate that macrophages can be activated in vitro by utilizing appropriate stimulating reagents, and that these activated macrophages have a potent antimetastatic effect.