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Ineffectiveness of adoptive chemoimmunotherapy with lymphokine-activated killer cells, interleukin-2, and cyclophosphamide on palpable intradermal murine bladder cancer.

The effects of adoptive immunotherapy with lymphokine-activated killer (LAK) cells and human recombinant interleukin 2 (IL2), on palpable intradermal (i.d.) bladder tumor were studied. The murine transitional cell carcinoma MBT-2 was used in C3H mice. IL2 was given intraperitoneally at 5,000 U/injection three times a day for 5 consecutive days beginning on day 10. LAK cells were generated in vitro from normal splenocytes: 10(7)-10(8) LAK cells were transferred intravenously on day 10 and, in some experiments, also on day 13. IL2 alone, LAK cells alone (total 8 x 10(7], and both in combination showed little or no influence on intradermally growing MBT-2 tumors. Cyclophosphamide was also combined with adoptive immunotherapy (IL2 and LAK). CY (100 mg/kg, i.p. on day 9 or 10) alone was able to suppress i.d. MBT-2 growth significantly. The combination treatment of IL2 and LAK cells with CY caused additional tumor growth suppression in a manner dependent on the total number of LAK cells transferred. The amount of the additional tumor growth suppression was, however, relatively small when compared with CY plus IL2-treated groups. In comparison, experimentally induced 3-day and 10-day pulmonary metastases of MBT-2 cells were treated by the same protocol of IL2 and LAK cells but without CY. IL2 alone reduced the number of gross metastatic nodules in the lung. The addition of LAK cells to the IL2 almost entirely eradicated the 3-day metastatic nodules but was less effective against the 10-day metastases. The data suggest that adoptive immunotherapy with IL2 and LAK cells mediates tumor regression of micrometastases at a selected organ (lung), but is ineffective against the same tumor growing in the skin or in gross metastatic nodules. Host immune suppression by CY was not beneficial in this model in creating a successful therapeutic effect of LAK cells and IL2.

Animals↗

[Study on adoptive immunotherapy for experimental brain tumor].

Adoptive immunotherapy for the experimental murine brain tumor has been investigated using LAK cells generated in vitro from normal spleen cells with IL-2 and immune spleen cells from Fischer rats immunized against syngenic gliosarcoma, T9. IL-2 inhibitor(s) activity in serum was also studied. LAK cells and immune spleen cells were adoptively transferred to the rats intravenously or intratumorally on the 7th day after the inoculation of T9 into the right basal ganglia. Then the survival rate and necrotic foci were compared between the groups treated with those cells and the control. The survival rate of the groups treated with LAK cells was significantly higher than that of the control (administrated intravenously; P less than 0.01, administrated intratumorally; P less than 0.05). But the treatment with immune spleen cells was not effective. The incidence and area of necrotic foci in the tumors treated with LAK cells were greater than those of the others. Microautoradiography was also performed using 3H-TdR labeled LAK cells, which were administrated intravenously to the model. It was revealed that LAK cells accumulated in lung shortly after the administration, then in liver and spleen, especially in the white pulp. IL-2 inhibitor activity of the sera from the tumor-bearers was greater than that of normal rats, while it was depressed markedly by cyclophosphamide (60 mg/kg i.p.). In conclusion, the adoptive transfer of LAK cells can be one of the effective and attractive treatments of the brain tumor. In order to make immunotherapy more effective it should be necessary to clarify the nature of IL-2 inhibitor(s).

Animals↗

Diffusion of an innovation: adoption of MRI.

"Diffusion of Innovation" is a marketing theory that predicts the pattern of adoption of new products, with specific characteristics of the product determining the rate of adoption. This article attempts to determine whether MRI fits the predicted pattern. A computer Medline search to assess the number of articles printed on MRI shows that MRI is being adopted more slowly than CT, but like CT, MRI is following the pattern predicted by the Diffusion Theory.

Communication↗

Adoptive immunotherapy by pantropic killer cells recovered from OK-432-injected tumor sites in mice.

A murine malignant ascites model with BAMC-1 tumors was established previously, which was cured completely by five consecutive i.p. injections of OK-432. We have found that peritoneal mononuclear cells from these animals contained antitumor effector cells which could destroy nonspecifically a variety of tumor cells in vitro. They were tentatively called pantropic killer cells (PKCs). The present study was essentially designed to show the antitumor effectiveness of the PKCs in vivo by the use of an adoptive immunotherapy model. The growth of BAMC-1 tumors transplanted s.c. 5 days earlier was significantly suppressed by passive transfer of 5 x 10(6) to 2 x 10(7) PKCs induced by injection of OK-432 into BAMC-1 bearing donor mice, while more than 1 x 10(8) immune spleen cells from the same donors treated with OK-432 were required to achieve the similar effects. Furthermore, if the tumor-bearing recipients were pretreated with 180 mg/kg of cyclophosphamide 1 h before the adoptive transfer, even 5 x 10(6) PKCs could induce complete regression of the tumors transplanted 5 days earlier. This protocol made it possible even to achieve the complete regression of larger tumors (9-10 mm in diameter) in recipients transplanted 12 days earlier. The PKCs were, as expected, able to cure not only BAMC-1-bearing animals but also Meth-A-bearing mice. As effector cells for adoptive immunotherapy, therefore, the PKCs induced by OK-432 seem to be as effective as, if not better than, lymphokine-activated killer cells expanded in vitro by culturing tumor infiltrating lymphocytes with interleukin-2. Although the study on surface markers of PKCs did not unequivocally discriminate these from lymphokine-activated killer cells, the present findings are considered significant indicating that a potent biological response modifier such as OK-432 can induce pantropic killer cells which are extremely effective in destroying various tumor cells in vivo. One of the advantages of OK-432 therapy over lymphokine-activated killer cell therapy, therefore, is that the former does not require the tedious and time-consuming in vitro procedures which are essential for the latter.

Animals↗

Adoptive transfer of autoimmune diabetes mellitus in biobreeding/Worcester (BB/W) inbred and hybrid rats.

Adoptive transfer of diabetes was accomplished by the injection of Con A-activated acutely diabetic BB/W rat spleen cells into immunosuppressed diabetes-resistant BB/W control rats and F1 hybrid offspring produced by BB/W X Lewis, BN, Yashida, and NEDH matings. Immune suppression methods that facilitated adoptive transfer of diabetes included neonatal thymectomy, cyclophosphamide, and splenectomy plus rabbit anti-rat lymphocyte serum injections. The successful transfer of BB/W diabetes to otherwise normal (BB/W X inbred)F1 rats and to diabetes-resistant BB/W animals suggests that antigenically normal pancreatic beta cells were destroyed by the injected effector cells. Diabetes-resistant BB/W control rats also evidenced diabetes after the injection of cyclophosphamide alone. The requirement for immunosuppression suggests that an intact immune system protects against adoptive transfer and diabetes in diabetes-resistant BB/W rats.

Animals↗

Diffusion of an innovation: adoption of CT scanners.

"Diffusion of Innovation" is a marketing theory that predicts the pattern of adoption of new products. The characteristics of an innovation and the "diffusion stages" of a new product as it moves toward widespread adoption are described. Then, the predictions of diffusion theory are compared to the pattern of adoption of CT.

Communication↗

Suppression of reaginic antibody formation. II. The use of adoptive transfer system for the study of immunological unresponsiveness.

By the use of the adoptive transfer system in syngeneic mice it was demonstrated that: i) spleen cells of animals tolerized by the i.v. injection of DNP8-MgammaG 1 month before adoptive transfer into x-irradiated recipients remained unresponsive when further challenged with the sensitizing antigen (DNP2.3-OA administered i.p. with Al (OH)3); by contrast, a significant response (typical of a secondary response) was obtained in recipients of cells from mice which had received only the sensitized antigen; ii) the anti-hapten IgE secondary response of primed cells was not affected by the presence of cells of tolerized mice when these two types of cells were administered and challenged together in x-irradiated recipients; iii) the transfer of spleen cells or serum of mice, tolerized 20 days before harvesting, into intact syngeneic recipients did not interfere with the normal development of the anti-DNP IgE response of the latter; iv) the anti-hapten responses of tolerized animals receiving spleen cells from normal or primed mice together with the sensitizing antigen resulted, respectively, in a primary or secondary response; (v) the unresponsive state of tolerized cells, achievkd by immunosuppression of the original donors with respect to the haptenic determinant, was maintained even after two serial exposures of the cells to the immunizing antigen in two consecutive adoptive cell transfers into x-irradiated recipients. These findings provide a strong basis for the interpretation that the hapten-specific tolerace induced in mice by treatment with DNP8-MphiG involved the elimination or inactivation of hapten-specific IgE-producing cells or the blockade of the receptors of these cells.

Animals↗

The effect of adoptive transfer of mononuclear leukocytes from an adult donor on spontaneous cell-mediated cytotoxicity and resistance to transmissible gastroenteritis in neonatal piglets.

The purpose of this study was to attempt to establish spontaneous cell-mediated cytotoxicity effector activity in the intraepithelial lymphocytes of neonatal piglets by adoptive transfer of mononuclear leukocytes from an adult donor and to determine the effect of transfer on the resistance of piglets to transmissible gastroenteritis. Cytotoxicity was determined by a chromium release assay using PK-15 cells persistently infected with transmissible gastroenteritis virus as targets. The experimental animals were inbred miniature pigs, in which a high degree of uniformity in lymphocyte defined histocompatibility complex antigens was demonstrated by the mixed lymphocyte reaction. Adoptive transfer of 8 X 10(7)-4 X 10(8) adult pig leukocytes established effector activity in eight recipient piglets, and leukocytes labelled with fluorescein isothiocyanate homed to the epithelium of the small intestine. When four recipients of 5 X 10(8) adult leukocytes were challenged with transmissible gastroenteritis virus, the onset of diarrhea was delayed for 24 h and the diarrhea was usually milder than in four untreated control piglets. It was concluded that the adoptive transfer of leukocytes with spontaneous cell-mediated cytotoxicity effector activity, which homed to the small intestinal epithelium, may have contributed to an increased resistance to transmissible gastroenteritis.

Animals↗

Cell-mediated immunity in experimental murine dermatophytosis. II. Adoptive transfer of immunity to dermatophyte infection by lymphoid cells from donors with acute or chronic infections.

An in vivo adoptive cell transfer system was used to investigate protective immunity during experimental murine dermatophytosis due to Trichophyton quinckeanum. Using sublethally (550R) irradiated BALB/c mice which are particularly susceptible to infection, it was found that regional lymph node cells from syngeneic acutely-infected donors conferred protection to irradiated recipients. By contrast, serum from the same donors did not prevent infection of normal BALB/c mice. The capacity of lymphoid cells to transfer adoptive immunity was lost after treatment with monoclonal anti-Thy-1.2 antibody and complement, but not after treatment with monoclonal anti-Ly 2.2 antibody and complement, indicating that cellular immunity is mediated by Ly 2-T cells. The cellular activity of chronically infected mice was also studied. Paradoxically, lymphoid cells from these animals which appeared to be immunologically compromised did, however, confer immunity. Adoptive immunity was abrogated by serum from chronically infected donors or by specific dermatophyte antigen, but not by homologous or heterologous anti-dermatophyte antiserum. These findings indicate that competition between cell-mediated immunity and humoral factors may be the causative mechanism for persistence of dermatophyte infection in this system.

Acute Disease↗

Adoptive immunotherapy of established syngeneic solid tumors: role of T lymphoid subpopulations.

We have investigated the subpopulations of T cells necessary to mediate the cure of established tumors in two models of successful adoptive immunotherapy. In C57BL/6 mice bearing palpable and disseminated FBL-3 lymphoma, both Lyt-1+ and Lyt-2+ cells played a major role in mediating the regression and permanent cure of mice, whereas in BALB/c mice bearing the Meth A sarcoma the adoptive transfer of Lyt-1+2+ cells played a major role in mediating the regression of tumors and the curing of disease. Identical experiments performed in hybrid (BALB/c X C57BL/6) mice yielded similar results, further supporting our initial observation and indicating that in these two adoptive transfer model systems it is the tumor and not the variable expression of Lyt antigens by the host that determines which T cell subpopulation is required to cure mice of tumors.

Animals↗

Adoption of tumor immunity: role of the major histocompatibility complex.

T cells from spleens of mice immunized against a chemically induced tumor were able, when transferred to normal syngeneic mice together with tumor cells, to protect adoptively against tumor growth. The inability of such cells to identically protect pangenic nude mice and F1 hybrid mice, and the incompetence of T cells alone in the in vitro tests indicated that the T cells by themselves were unable to kill the tumor cells. We hypothesized that the protection transmitted by spleen T cells results from an interaction with the recipient mouse and that this interaction is controlled by the major histocompatibility complex (MHC). Analysis of the lack of protection at the level of the MHC subregion demonstrated that in the transfer of immune spleen T cells from parent mice to F1 recipient mice, an identity of the KIA subregion permitted a complete transfer of protection. In the transfer of immune spleen T cells from F1 mice to parent recipients, a semi-identity of the KIA subregion was sufficient but a complete identity of the H2D subregion was necessary. The use of such a model, requiring the transfer of parental cells to F1 hybrid mice, necessitated the analysis of the possible role of the hybrid resistance gene. We have demonstrated the absence of correlation between the hybrid resistance and the adoptive protection. At the present stage of this work, the adoptive neutralization test allows us to conclude that the immunologic rejection of a chemically induced tumor is the result of interaction between 2 cells, a T cell and a radioresistant non-T cell.

Animals↗

Systemic adoptive transfer of immunity to 13762A rat mammary adenocarcinoma.

Rats cured of metastatic 13762A rat mammary adenocarcinoma by Corynebacterium parvum immunotherapy possess strong tumor-specific rejection immunity. Systemic adoptive transfer of lymphoreticular cells from cured rat donors conferred protective immunity on naive recipients. Fewer oil-induced peritoneal exudate cells than lymph node cells were required to transfer tumor rejection immunity. The adoptive immunity was specific since it strongly inhibited 13762A tumor growth but did not inhibit the growth of the antigenically unrelated R3230AC rat mammary tumor. Rats sensitized to the bacterial immune stimulant used to effect cure were unsuitable donors of PEC capable of transferring tumor rejection immunity. Macrophages or bone marrow-derived lymphocytes from immune donors did not transfer immunity. Treatment of peritoneal exudate with a xenogeneic antiserum specific for rat thymus-derived lymphocytes significantly reduced the efficiency of transfer. We conclude that thymus-derived lymphocytes from rats cured of 13762A tumor were required for the adoptive transfer of tumor-specific rejection immunity.

Adenocarcinoma↗

Differential requirement for B-memory and T-memory cells in adoptive antibody formation in mouse bone marrow.

During the secondary response of mice to T-dependent antigens, antibody-producing plaque-forming cells (PFC) appear not only in peripheral lymphoid organs, but also in the bone marrow. This bone marrow antibody formation is feeble after primary immunization. The capacity of bone marrow antibody formation is dependent on the presence of antigen-specific memory cells at the moment of secondary immunization. We investigated whether hapten-primed B memory, carrier-primed T memory or both B-memory and T-memory cells are required for the adoptive PFC response in the bone marrow to T-dependent hapten-carrier conjugates. Adoptive antibody formation in the bone marrow was found after transfer of hapten-primed spleen cells, but not after transfer of carrier-primed spleen cells or virgin spleen cells. Thus, B-memory cells are obligatory for adoptive antibody formation in the bone marrow, in contrast to T-memory cells. However, T-memory cells did facilitate the bone marrow PFC response mediated by the infused B-memory cells.

Animals↗

In vitro growth of murine T cells. VI. Accelerated skin graft rejection caused by adoptively transferred cells expanded in T cell growth factor.

The ability of adoptively transferred cytotoxic T cells expanded in T cell growth factor (TCGF) to induce accelerated graft rejection of B10.BR skin grafts from normal B6AF1 recipient mice was tested. In vitro sensitized cells expanded in regular TCGF were capable of accelerating graft rejection when adoptively transferred i.v. 1 day after grafting. Cells expanded in LF-TCGF (lectin-free) were more effective in accelerating graft rejection than cells expanded in lectin containing TCGF. Nonsensitized cells or cells sensitized to irrelevant B10.D2 antigenic determinants in vitro and subsequently expanded in LF-TCGF were unable to induce accelerated rejection of the B10.BR grafts. Expanded cytotoxic effector cells known to be immunologically active in vivo were also unable to accelerate graft rejection if irradiated with 2000 R before adoptive transfer. The ability of cells to lyse the appropriate targets in 4-hr 51Cr release assays correlated poorly with the effectiveness of these cells after in vivo injection. These studies are the first to demonstrate that cytotoxic cells expanded in TCGF are capable of mediating a cytotoxic function in vivo.

Animals↗

Regulation of the expression of adoptive tumor rejection immunity by recipient cyclophosphamide-sensitive cells.

Peritoneal exudate T-cells from rats immune to 13762A rat mammary tumor conferred specific tumor rejection immunity on normal recipients. The efficiency of systemic adoptive transfer of tumor rejection immunity with immune peritoneal exudate T-cells was improved by cyclophosphamide (CY) pretreatment of recipients. Optimal potentiation was obtained with a dose of 50 or 100 mg CY per kg body weight given the day before transfer. CY pretreatment of recipients was effective 1 to 3 days prior to transfer. The CY-potentiating effect was lost with longer intervals between CY administration and transfer, indicating recipient recovery. CY pretreatment enabled recipients to reject greater numbers (100 times) of tumor cells and inhibited tumor challenge established before systemic adoptive transfer. The CY-induced potentiation of systemic transfer of tumor immunity was reversed by i.v.-administered normal spleen. We concluded that CY-sensitive host regulatory cells restricted the expression of adoptive tumor rejection immunity. Control of the activity of these regulatory cells allows increased efficacy of effector T-lymphocytes in this system.

Animals↗

Adoptive transfer of total and parasite-specific IgE responses in rats infected with Nippostrongylus brasiliensis.

Infection of rats with Nippostrongylus brasiliensis has both a parasite-specific and non-specific IgE stimulating effect. Both these responses can be adoptively transferred with thoracic duct lymphocytes (TDL) from infected rats. The character of the IgE response in the recipient rats was related to the stage after infection of the cell donors. TDL from hyperimmune rats adoptively transferred high serum titres of parasite-specific IgE to infected recipient rats and substantially increased the levels of total IgE. However, adoptive immunization with TDL from donors infected 10 days previously did not stimulate parasite-specific IgE and only slightly increased total IgE levels. After cell fractionation the sIg- cells from day 10 TDL increased the level of total IgE but not parasite-specific IgE whereas sIg- cells from hyperimmune TDL did not induce any IgE response unless given with sIg+ cells. The possible reasons for this are discussed.

Animals↗

Quantitative aspects of abolition of transplantation tolerance by the adoptive transfer of lymphoid cells.

It was found that with neonatally induced transplantation tolerance about 50% of the rats are insensitive, or little sensitive, to the adoptive transfer of immunity. The proportion of rejected and unrejected skin grafts in individual experiments did not show a direct dependence on the dose of transferred cells, and immune lymphocytes were as effective as non-immune cells. No dependence on the time post-transplantation was found. Only the results of the adoptive transfers performed after more than 120 days after transplantation indicated an increased resistance of the tolerant state. Also repeated transfers in which increasing doses of cells were used showed a relatively stable state of tolerance in some animals. It is discussed that the difference in the sensitivity to the adoptive transfer might reflect at least quantitative individual differences in the mechanism of the state of unresponsiveness in neonatally induced tolerance.

Animals↗

Predictors of nurse adoption of a computerized information system as an innovation.

This descriptive study focused on factors that influence the diffusion and adoption of an innovation after it is first introduced to members of a social system. The purposes of the study were 1) to explore a set of individual, technological, and organizational characteristics as predictors of hospital nurse adoption of a computerized information system (CIS) as an innovation, and 2) to investigate the effect of organizational position on innovation adoption. A computerized nursing information system for staffing, scheduling and productivity management was selected as the innovation.

Attitude to Computers↗