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N R Pellis

Publications and source records attributed to N R Pellis.

At least 55 records · Page 3Linked to original sources
PubMed1987

Muramyl tripeptide: an effective immunotherapy in the surgical setting for pediatric abdominal neoplasms.

A potential complication of intraperitoneal neoplasms is the occurrence of peritoneal metastases. This experiment hypothesizes that resident peritoneal macrophages, activated by muramyl tripeptide (MTP-PE), will destroy peritoneal tumor. MTP-PE is a lipophilic derivative of the mycobacteria cell wall component responsible for induction of cellular immunity and activation of macrophages to a tumoricidal state. A transplantable murine fibrosarcoma, MCA-F was utilized. Murine hosts were challenged intraperitoneally with 5 X 10(3) MCA-F cells. Treatment with MTP-PE micelles or liposome-encapsulated MTP-PE was initiated 48 hours prechallenge and on the day of tumor challenge and continued at 72 hour intervals for the subsequent 21 days. Hosts were observed for survival. At 45 days after tumor challenge, all untreated control animals had succumbed to overwhelming neoplastic disease. In contrast, 30% of the mice treated with liposome-encapsulated MTP-PE (P less than .05) and 50% of the animals treated with MTP-PE micelles (P less than .001) remained alive at 60 days. Followed for 120 days, 20% of MTP-PE micelle treated mice are long-term survivors. These results suggest that control of intraperitoneal seedings may be achieved with MTP-PE when the tumor burden is small.

Abdominal Neoplasms↗
PubMed1986

Specific chemoimmunotherapy in tumor-bearing mice with extracted antigen, cyclophosphamide, and intrasplenic administration of interleukin-2.

The effect of daily intrasplenic (I-SP) injection of interleukin-2 (IL-2) in conjunction with specific chemoimmunotherapy with extracted tumor antigens and cyclophosphamide was assessed with the use of methylcholanthrene (MCA)-induced fibrosarcoma in C3H/HeJ mice. Injections of 80 U of human IL-2 were delivered transcutaneously into the spleen (I-SP), which had been relocated to the subcutis with its blood supply intact. Six daily I-SP injections into mice bearing MCA-F tumors activated immune spleen cells (SPC), as evidenced by specific neutralization of the MCA-F, but not the antigenically different MCA-D tumor, in local adoptive transfer assays. The immune cell phenotype was Thy 1.2+ Lyt 2+, based upon abrogation of tumor neutralization after depletion with monoclonal antibodies and complement. In a second series of experiments, primary hosts bearing established MCA-F tumors underwent therapy with 1 microgram 1-butanol extracted, isoelectrophoretically purified TSTA injected subcutaneously, a single intraperitoneal (IP) dose of 20 mg/kg cyclophosphamide (CY), and/or either IP or I-SP IL-2 injection. Triple chemoimmunotherapy with I-SP, but not IP, IL-2 retarded tumor outgrowth more effectively than single or double treatment protocols. Furthermore, in a third series of investigations, the triple therapy group showed both decreased numbers and incidence of spontaneous metastases from a subcutaneous implant of clone 9-4, a highly metastatic variant of MCA-F. Indeed, 35% of hosts that received triple therapy, but none of the animals treated with other regimens, were free of lung metastasis (P less than 0.02). Thus, tumor resistance engendered by chemoimmunotherapy with TSTA and CY is potentiated in vivo by I-SP administration of IL-2.

Animals↗
PubMed1986

Continuous intrasplenic interleukin-2 combined with antigen-specific chemoimmunotherapy.

A methylcholanthrene-induced fibrosarcoma model in C3H/HeJ mice demonstrated that combined chemoimmunotherapy, including partially purified, 1-butanol-extracted, tumor-specific transplantation antigen (1 microgram), cyclophosphamide (20 mg/kg), and continuous intrasplenic (IS) or intravenous (IV) infusion of purified human interleukin-2 (IL-2) (120 U/d) reduced the outgrowth of 4-mm established tumors, while IL-2 alone only modestly decreased tumor growth. For tumors larger than 1 cm, only the triple regimen with IS IL-2 significantly inhibited tumor growth, whereas IL-2 alone or the triple regimen with IV IL-2 failed to retard tumor growth. Furthermore, the first regimen significantly decreased pulmonary metastases after primary tumor resection. The Lyt-2+ phenotype predominated in the effector population of animals treated with this regimen, while L3T4+ cells predominated in those treated with the triple regimen that included IV IL-2. Thus, continuous IS IL-2 administration potentiates the efficacy of antigen-specific chemoimmunotherapy.

Animals↗
PubMed1986

Suppression of the induction of delayed hypersensitivity in rats by repetitive morphine treatments.

Previous in vitro experiments suggest that lymphocyte function may be altered in the presence of opiates. The effect of morphine treatment upon specific T lymphocyte function in vivo was investigated in rats. Following morphine treatment, rats were incapable of responding to immunization with the T-dependent antigens of Mycobacterium bovis, strain BCG. The absence of a delayed hypersensitive skin response to tuberculin in chronic morphine-treated rats supports the hypothesis that opiates may interact with the cells of the immune system. A potential communication between the nervous system and cells of the immune system is proposed.

Animals↗
PubMed1986

Evidence that opiate addiction is in part an immune response. Destruction of the immune system by irradiation-altered opiate withdrawal.

Experiments were performed to determine whether physical dependence on opiates (CNS phenomena) can be altered by destruction of the immune system. Irradiation, prior to or after chronic treatment with morphine significantly reduced the opiate-withdrawal syndrome as assessed by naloxone-induced abstinence. This study supports the proposition that addiction to opiates is related, at least in part, to interaction between the central nervous system (CNS) and the immune system.

Animals↗
PubMed1986

Intrasplenic administration of interleukin-2 to potentiate specific chemoimmunotherapy in tumor-bearing mice.

Augmentation of specific chemoimmunotherapy by daily, intrasplenic injection of interleukin-2 (IL-2) was assessed in a methylcholanthrene (MCA)-induced fibrosarcoma model in C3H/HeJ mice. Daily access to the spleen was achieved by relocating the organ into the subcutis while leaving its blood supply intact. Following intrasplenic injection of 80 units of human IL-2 into MCA-F tumor-bearing mice for 6 days, spleen cells tested in the local adoptive transfer assay showed specific neutralization of MCA-F, but not the antigenically different MCA-D, tumor. Depletion of the spleen cell population with monoclonal antibodies and complement showed that the responding cell bore the surface markers Thy 1.2 and Lyt 2. Mice bearing established MCA-F tumors underwent a variety of chemoimmunotherapy regimens, including 1 microgram of 1-butanol, extracted isoelectrophoretically purified tumor-specific transplantation antigen, a single i.p. dose of cyclophosphamide (20 mg/kg), and/or either i.p. or intrasplenic injection of 80 units of IL-2. Specific triple chemoimmunotherapy including daily intrasplenic IL-2, but not i.p., administration was superior in the degree of tumor neutralization to all single or double therapy protocols. Furthermore, the combined triple modality inhibited spontaneous lung colonization by clone 9-4, a highly metastatic variant of MCA-F; both the numbers of lung colonies (median, 17; range, 2 to 55, versus median, 3, range, 0 to 42; P less than 0.005) and the incidence were decreased. The combined treatment group displayed 35% of hosts free of lung metastasis, while 100% of the control animals had lung colonies (P less than 0.02). Thus antitumor immunity was augmented in vivo using IL-2 delivered by intrasplenic, but not i.p., injection. Furthermore, chemoimmunotherapy including intrasplenic IL-2 injection potentiated the antitumor immunity achieved with combined tumor-specific transplantation antigen and cyclophosphamide.

Animals↗
PubMed1986

Effects of concomitant and sinecomitant immunity on postsurgical metastasis in mice.

The role of concomitant and sinecomitant antitumor resistance in the regulation of metastatic outgrowth was assessed using methylcholanthrene (MCA)-induced tumors in C3H/HeJ mice. Variants of neoplasms MCA-F, MCA-D, and MCA-2A were selected for proclivity for spontaneous lung metastasis and expression of parental tumor-specific transplantation antigens. The incidence of spontaneous lung metastases after resection of a s.c. tumor of clone 9-4, a highly metastatic variant of the MCA-F tumor, was determined by both the size and the duration of neoplastic disease. The coexistence of the primary local tumor retarded lung colonization both from spontaneous and after artificially induced metastases. Greater concomitant immunity leading to a reduced number of artificial metastases after i.v. challenge with clone 9-4 cells was evident in hosts bearing large (1.6 to 1.8 cm) compared to small (0.1 to 0.2 cm) burdens of the nonmetastatic MCA-F (P less than 0.005). Furthermore, i.v. challenge of mice bearing antigenically different tumors revealed that the concomitant inhibition was antigen specific with small tumor burdens, but nonspecific and possibly more efficacious with large tumor burdens. Therefore, concomitant antimetastatic immunity consists of both specific, immune-mediated resistance and nonimmunological mechanisms. Specific concomitant immunity decreases inversely with the progression of the primary, while nonimmunological inhibition of metastasis increases during late stages of primary growth. Abrogation of the strong nonspecific concomitant inhibition by resection of the primary tumor may facilitate lung metastasis. On the other hand, significantly greater inhibition of metastases occurred after resection of 7- or 14-day neoplasms compared to larger tumors (P less than 0.001 or 0.05). Sinecomitant inhibition is antigen specific, probably representing an extension of specific concomitant immunity. These results suggest that adjunctive immunotherapeutic protocols for surgically treated hosts should augment existent specific immunity and promote nonspecific resistance, in order to minimize metastatic outgrowth.

Animals↗
PubMed1985

Antigen-specific therapy of experimental metastases.

In a methylcholanthrene-induced tumor (MCA-F) model in C3H/HeJ mice, curative resection of a progressive tumor promotes artificial lung metastases following intravenous injection of a highly metastatic cell variant designated clone 9-4. The number of metastatic lung colonies depends upon the status of host immunity at the tumor resection: mice resected 7 or 14 days, but not 28 days after tumor inoculation display significantly retarded postoperative, experimentally induced lung metastases. The number of lung colonies in mice that had tumors resected at 14 days was three times greater than in mice that had 28-day neoplasms resected. Neither therapy with weekly injection of 50 micrograms tumor-specific transplantation antigen, which had been extracted using a single phase of 2.5% 1-butanol (CBE), nor 20 mg/kg cyclophosphamide (CY) alone prevented lung colonization. Assessment of helper-suppressor ratios in the spleen from mice after tumor surgery showed that CBE administration decreased the ratio in mice after resection of 14-day tumors, but not after resection of 28-day tumors. Combined therapy with specific tumor antigen and an antisuppressor cell agent reduced metastases, regardless of the tumor size.

Animals↗
PubMed1985

The effect of purification on the immunogenicity of tumor-specific transplantation antigens.

Immunization with the tumor-specific transplantation antigens (TSTA) of experimental, chemically induced sarcomas engenders specific host resistance to challenge with viable, homotypic neoplastic cells. The strength of tumor resistance depends upon the physical state of the TSTA used for immunization. Treatment with 10(5)-10(6) irradiated tumor cells, a 2-log dose range, induces complete rejection of neoplastic challenges, while immunization within a 1-log dose range with crude 3 M KCl or with 2.5% butanol extracts containing TSTA evokes a weak state of resistance characterized by decreased outgrowth of tumor challenges, but not neoplastic regression. The reduced immunogenicity may be due to either contamination with substances that antagonize host resistance, for example by induction of suppressor cells, or an intrinsic limitation by virtue of the molecular properties of extracted compared with cell-surface TSTA. MCA-F and MCA-D, two noncross-reactive fibrosarcomas induced in C3H/HeJ mice with 3-methylcholanthrene, were employed to compare the relative immunogenic activity of intact tumor cells, 2.5% butanol extracts, and materials sequentially purified by preparative isoelectric focusing (pIEF), preparative isotachophoresis (pITP), and high performance gel permeation chromatography (HPGPC). Immunoprotective TSTA activity purified 50,000-fold by this protocol extended the effective dose range by four to five logs: 15 pg to 1.5 micrograms MCA-F or 1 pg to 10 ng MCA-D antigen-induced specific host resistance. However, despite the appreciable purification of TSTA, immunization with extracted materials only delayed neoplastic outgrowth. They induced neither immediate rejection nor only temporary progression of transplanted tumor cells. Thus, purified TSTA preparations by themselves lack the immunogenic properties of intact cells that result in maximal induction of tumor resistance.

Animals↗
PubMed1985

Induction of suppressor cells by a tumor-derived suppressor factor.

Murine fibrosarcomas produce a factor that activates suppressor cells to inhibit expression of delayed-type hypersensitivity (DTH) responses to dinitrochlorobenzene (DNCB). This tumor-derived suppressor factor (TDSF) was partially purified by preparative isoelectric focusing of spent medium and 3 M KCl extracts of cultured methylcholanthrene-induced and spontaneous fibrosarcomas of C3H/He mice. Incubation of 1 micrograms/ml of a fraction, isoelectric pH less than 2.9, with normal syngeneic spleen cells for 1-6 hr at 37 degrees C induced suppressor cells that inhibited the primary DTH response to DNCB upon intraperitoneal transfer to normal C3H/HeJ mice. TDSF was not present in extracts of either syngeneic embryonic fibroblasts or normal spleen cells or in medium conditioned by normal peritoneal exudate cells but was present in 3 M KCl extracts of and the spent medium from four different cultured murine fibrosarcomas. TDSF activity was not restricted at the major histocompatibility complex. The suppressor cells inhibited the efferent limb of the DTH response because (1) hyporesponsive recipients of TDSF-treated spleen cells had splenic effector T cells capable of transferring DTH to DNCB into naive secondary recipients and (2) the ability of Lyt 1+,2- effector Tdth cells to transfer a secondary DTH response to DNCB was inhibited by co-incubation with macrophages or Lyt 1-,2+ T cells treated with TDSF. Preliminary biochemical analysis suggested that TDSF was an RNA- protein complex. Thus, several murine fibrosarcomas produced a soluble factor that activated splenic suppressor cells to depress the immune response to nonneoplastic antigens. These suppressor factors represent a novel group of regulatory molecules which may be ribonucleoprotein complexes.

Animals↗
PubMed1985

Biochemical characterization of 1-butanol-extracted murine tumor-specific transplantation antigens.

This investigation sought to characterize biochemically the tumor-specific transplantation antigens (TSTA) expressed on the cell surface of a panel of chemically induced fibrosarcomas of C3H/HeJ mice. Results suggest a uniform antigenic framework upon which individual specificities are superimposed. The antigens expressed by the 3-methylcholanthrene-induced fibrosarcomas MCA-D, MCA-F, and MCA-2A fulfill the requirements of a TSTA; namely, immunization of syngeneic hosts with irradiated cells or soluble extracts engenders a tumor-specific immune response such that animals resist challenge with the same, but not another, tumor. Brief incubation of intact tumor cells in single-phase aqueous solutions of 2.5% (v/v) 1-butanol extracts an immunoprotective TSTA, but not alloantigenic activity, from MCA-F cells. This extraction protocol was extended to the two other MCA-induced neoplasms. The butanol-extracted TSTA from the three tumors displayed isoelectric pHs of 6.4 to 6.6 following preparative isoelectric focusing. The tumor-specific immunoprotective activity from all three tumors displayed an apparent molecular weight of 150,000 (150 kDa) during high-performance gel permeation chromatography. The chromatographic properties of the 150 kDa antigens were unaffected by reduction using dithiothreitol, but incubation in acetate buffer, pH 3.0, dissociated the 150 kDa complex into at least two components with molecular weights of 70 to 100 kDa and 20 to 40 kDa. Only the smaller component displayed TSTA activity. The presence of two major components in the 150-kDa antigen was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. TSTA activity was sensitive to digestion with pronase, papain, chymotrypsin, and alpha-mannosidase, but resistant to DNase, RNase, neuraminidase, trypsin, endoglycosidase H, and a mixed-function glycosidase. In addition, the TSTA activity was unaffected by heating. These data demonstrate that MCA carcinogenesis results in the expression of immunologically unique epitopes on biochemically related glycoproteins and suggest a unified mechanism for the generation of TSTA polymorphism.

1-Butanol↗
PubMed1984

The role of the spleen in tumor bearing host: I. Characterization of spleen cells in tumor-bearing mice.

Morphologic changes of the spleen and dynamic changes of biologic activity of spleen cells from C3H/HeJ mice bearing methylcholanthrene induced fibrosarcoma (MCA-F) were investigated in different stages of tumor growth, using local adoptive transfer assay (LATA). The spleen size, weight and the number of spleen cells increased with the tumor growth. In early and late stages of tumor growth, tumor-bearing mice possessed non-specific tumor-enhancing cells which were radioresistant (700 rads), phagocytic and adherent, suggesting that they were macrophages. On the other hand, in middle stages of tumorgenesis, tumor-bearing mice possessed specific cytotoxic cells which were radiosensitive (700 rads) and anti-Thy 1.2 serum positive, suggesting that they were T-cells. Thus, the appearance of tumor-enhancing cells was earlier than cytotoxic cells in MCA-F bearing host, and the balance of tumor-enhancing and cytotoxic cells may influence the tumor outgrowth in different stages of tumorgenesis. The spleen serves as a reservoir of factors which either abrogate cell mediated resistance or stimulate neoplastic growth, or as the source of cytotoxic cells, at certain times of tumor burden.

Animals↗
PubMed1984

The role of the spleen in tumor bearing host: II. The influence of splenectomy in mice.

The effect of splenectomy on neoplastic outgrowth was examined prior to and after implantation of methylcholanthrene-induced C3H/He murine tumors. Splenectomy performed 12 days before tumor inoculation did not affect the tumor outgrowth, however, both splenectomy and sham operation performed shortly before tumor inoculation resulted in significant tumor facilitation compared with the non-operated group, suggesting that this accelerated tumor was not related to the presence or absence of splenic tissue, but rather to systemically-induced immunosuppression. While splenectomy performed 6, 9, 12 days after tumor inoculation did not alter the tumor growth, splenectomy performed early (3 days) or late stage (20 days) after tumor cell challenge revealed a retarded neoplastic outgrowth, compared with the sham operated group. These results suggest that splenectomy in very early and late stages of tumor-bearing host may be effective for tumor treatment.

Animals↗
PubMed1984

Soluble factors from murine and human tumors induce suppressor cells.

A tumor-derived suppressor factor ( TDSF ) has been isolated from 3 M KCl extracts of a chemically induced fibrosarcoma of C3H/HeJ mice by preparative isoelectric focusing. Incubation of TDSF with normal spleen cells induces suppressor cells that enhance tumor growth and inhibit DTH to the chemical sensitizer 2,4-dinitro-1-chlorobenzene (DNCB). Similar suppressogenic activity has been detected in extracts of the 10T1/2 fibroblast line, an ultraviolet-induced fibrosarcoma of C3H/HeN mice, the C57B1/6J Lewis lung carcinoma, and four human colonic adenocarcinoma. TDSF activity was not found in extracts of syngeneic muscle or spleen cells. Chemical characterization of TDSF from the murine fibrosarcoma MCA-F revealed sensitivity to treatment with heat and RNase, partial sensitivity to treatment with trypsin, but resistance to treatment with DNase, pronase, and neuraminidase. TDSF has an apparent molecular weight of greater than 300 kDa by high-performance gel permeation chromatography. Acidic soluble factors isolated from murine and human tumors induce suppressor cells to inhibit cell-mediated immunity in an intact host.

Adenocarcinoma↗
PubMed1984

Retardation of postsurgical metastases with the use of extracted tumor-specific transplantation antigens and cyclophosphamide.

In a 3-methylcholanthrene [(MCA) CAS: 56-49-5]-induced tumor model of C3H/HeJ mice excision of a growing primary tumor decreased concomitant immunity and facilitated experimental lung metastases. Administration of tumor-specific transplantation antigens extracted from viable MCA-F cells with the use of single-phase (2.5%) 1-butanol [crude butanol extract (CBE)] augmented immunity after resection of the primary MCA-F tumor. Two weeks after footpad inoculation of 2 X 10(5) MCA-F cells, the tumor-bearing limbs were amputated and the mice were challenged subsequently with 5 X 10(4) cells of clone-9-4, a metastatic variant of MCA-F, via the tail vein. Whereas treatment with either 50 micrograms CBE sc or 20 mg cyclophosphamide (CY)/kg ip failed to retard lung colonization, combination therapy with the two agents reduced the incidence of lung colonies by 69.8% (26.5 vs. 8; P less than .001) compared with the incidence in the surgery-alone group and by 55.5% (18 vs. 8; P less than .001) compared with the incidence in the group treated with surgery and CY. Furthermore, the combined effects of CBE and CY were immunologically specific: The combined therapy with the non-cross-reactive MCA-D-CBE did not protect against iv challenge with clone-9-4. Treatment with antigenic extracts induced a 21.4% (4.2 vs. 3.3%) decrease in the ratio of Lyt 1+:Lyt 2+ cells in the spleens of tumor-resected mice, which suggested restoration to normal levels. Therefore, in the combined regimen, antigen may induce specific activation of helper lymphocytes, while CY inhibits activation of suppressor cells.

Animals↗
PubMed1983

The effect of immunotherapy with extracted tumor antigens on sinecomitant immunity.

The fate of hosts after tumor resection depends upon the level of their sinecomitant immunity, which can destroy residual neoplastic cells. In addition, active specific immunotherapy can stimulate the resistance of mice incompletely resected of large tumors and therefore destined to develop recurrent disease. The studies presented herein, assessing host resistance by in vivo tumor challenge and an in vitro growth inhibition assay (GIA) measuring the effect of splenic lymphocytes on 3H-thymidine incorporation into monolayers of sarcoma cells, revealed an antagonistic relationship between sinecomitant immunity and tumor antigen immunotherapy. Treatment of hosts bearing high levels of endogenous sinecomitant immunity with Fraction 15 pI 5.95 partially purified from 3 M KCl extracts by preparative isoelectric focusing, decreased their resistance to tumor challenge and the capacity of their spleen cells to perform in the in vitro GIA. When sinecomitant immunity was not demonstrable, therapy with tumor antigen induced host resistance. If therapy was delayed until sinecomitant immunity had naturally waned, hosts displayed improved resistance toward secondary challenge. These findings suggest that not only does antigen therapy effect tumor resistance by a mechanism independent of sinecomitant immunity, but also these two mechanisms are mutually antagonistic. Therefore, the design of active specific immunotherapy protocols utilizing tumor antigens may depend on the level of the host endogenous sinecomitant resistance.

Animals↗