Biomedical subjects

M Rodrick

Publications and source records attributed to M Rodrick.

9 recordsLinked to original sources

PubMed1991

The systemic complement activation caused by interleukin-2/lymphokine-activated killer-cell therapy of cancer causes minimal systemic neutrophil activation.

Twenty-three cancer patients undergoing therapy with interleukin-2 and lymphokine-activated killer cells were studied for evidence of complement activation and systemic neutrophil activation occurring during the course of therapy. Patient plasma samples demonstrated evidence of marked complement activation, with 3-fold elevations of C3a desArg concentrations by the 8th day of therapy. Concentrations of C4a desArg were also elevated by the end of therapy. In vitro chemotaxis of patients' neutrophils both to C5a and to the synthetic peptide chemotaxin, FMLP, was initially normal and then fell progressively to 60% of normal by the end of treatment. Mean neutrophil cell-surface expression of complement receptor Type 1 and complement receptor Type 3 increased in inverse temporal relationship to the deficit in chemotaxis, but showed no consistent pattern for individuals and was only doubled at maximum. Thus, despite a degree of complement activation which should have produced pronounced neutrophil activation, the response of the circulating neutrophils was diminished. In view of this discrepancy, the toxicity of this therapy may not be mediated by activation of circulating neutrophils.

Chemotaxis, Leukocyte↗

PubMed1987

Three forms of BRP-2 (bone resorptive proteins) from human cancer ascites fluid and their relationship to human serum alpha-2 HS-glycoprotein.

Two new forms of BRP-2, a previously described bone resorptive protein, were purified from ascites fluids obtained from patients with hypercalcemia and metastatic bone cancer. The apparent molecular weights of BRP-2 and of these two proteins were 52,000, 48,000, and 46,000, respectively, as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The three proteins have essentially the same amino acid compositions but differ with respect to their carbohydrate moieties. The amino-terminal amino acid sequences of the three glycoproteins were identical to each other as well as to human serum alpha 2HS-(human serum) glycoprotein. The relationship of the three forms of BRP-2 to alpha 2HS was also established immunochemically. The ascites proteins, as well as alpha 2HS, on a molar basis, were approximately one-tenth as potent as bovine parathyroid hormone fragment (1-34) in their abilities to stimulate calcium release from bone in vitro. This study describes for the first time a possible function for human serum alpha 2HS.

Amino Acid Sequence↗

PubMed1986

Neutrophil activation in thermal injury as assessed by increased expression of complement receptors.

We studied neutrophil activation in patients with burns by serial immunofluorescent measurement of neutrophil expression of the complement opsonin receptors CR1 and CR3. CR1-dependent fluorescence was initially (days 0 through 5 after the burn) elevated (mean +/- SEM, 294 +/- 42 vs. 63 +/- 6 in the controls; P less than 0.001) and gradually returned to normal (days 6 through 8, 270 +/- 62, P less than 0.001; days 9 through 13, 185 +/- 38, P less than 0.001; days 14 through 19, 143 +/- 27, P less than 0.001; and days 20 through 50, 93 +/- 5, P less than 0.04). CR3-dependent fluorescence paralleled that of CR1. Neutrophil chemotaxis in response to zymosan-activated serum, a source of C5a, was depressed (days 0 through 5, 77 +/- 4 percent of control, P less than 0.001; days 6 through 8, 70 +/- 4 percent, P less than 0.001; days 9 through 13, 74 +/- 3 percent, P less than 0.001; days 14 through 19, 90 +/- 4 percent, P less than 0.01; and days 20 through 50, 97 +/- 3 percent, P not significant) and inversely correlated with CR1- and CR3-dependent fluorescence (r = -0.559, P less than 0.001; and r = -0.709, P less than 0.001, respectively). Plasma C3a desArg levels were above normal (100 +/- 5 ng per milliliter) throughout (days 0 through 5, 305 +/- 42; days 6 through 8, 546 +/- 69; days 9 through 13, 490 +/- 72; days 14 through 19, 409 +/- 54; and days 20 through 50, 260 +/- 36; all P less than 0.005). Thus, neutrophils in burned patients were activated as indicated by increased expression of complement receptors. The correlation between this increase and the depression of chemotaxis in response to zymosan-activated serum suggests that C5a is responsible for systemic neutrophil activation, which may contribute to the increased susceptibility to infection of patients with burns.

Adult↗

PubMed1985

Interleukin generation in experimental colon cancer of rats: effects of tumor growth and tumor therapy.

The capacity of inbred W/Fu rats bearing syngeneic colon carcinomas to generate interleukin(s) (IL) was studied during primary tumor growth, after tumor resection, and during postresection immunotherapy. During local tumor growth, there was a significant decrease in the capacity of the host's adherent mononuclear cells to generate IL-1 and of peripheral blood mononuclear cells to generate IL-2 (16.6 and 23%, respectively, when compared to control animals; P less than .01). The presence of regional metastases or large primary tumor burden resulted in a further sharp fall in IL generation (0.9 and 10% for IL-1 and IL-2, respectively, when compared to control animals; P less than .01). With the use of three different doses of tumor inoculum, inhibition of IL generation was shown to occur when tumors were barely palpable. Decrease in IL correlated with tumor growth and not with the initial number of tumor cells injected. Tumor resection resulted in a rise in IL-2 generation from 36 to 64% of control animals' levels. Postresection immunotherapy with the use of an active specific immunization protocol successfully modulated IL-2 production to normal in animals protected from tumor recurrence. Animals that developed recurrent tumors despite immunization exhibited a continued inability to generate IL (mean values of IL-2 production compared to controls: 184% in animals free of recurrence after immunotherapy, 1% in animals developing recurrent tumors after immunotherapy; P less than .01). These results suggested that alterations in IL generation may lead to immune unresponsiveness during tumor growth. Active specific immunotherapy protecting animals from recurrence after primary tumor resection may be predicated on the successful modulation of IL level generation by host immunocytes.

Adenocarcinoma↗

PubMed1984

Effects of tumor growth on interleukins and circulating immune complexes. Mechanisms of immune unresponsiveness.

This study delineates the temporal relationship between immune complex formation and tumor growth, and provides one possible explanation for host immunosuppression during tumor growth. The authors have studied serial circulating immune complex (CIC) levels and interleukin (IL) elaboration by peripheral blood cells (IL-1 production by adherent mononuclear cells [AMC]; and IL-2 generation by peripheral blood mononuclear cells [PBMC]) during the growth of syngeneic tumor isografts in an inbred rat model. Male Wistar/Furth (W/Fu) rats were injected, subcutaneously (SC) with 2 X 10(6) W163 ( a dimethylhydrazine [DMH]-induced colon adenocarcinoma) cells into their hind limbs. Serial CIC levels, (measured by the antigen nonspecific polyethylene glycol turbidity assay) and IL-1 and IL-2 production were measured before isografting and weekly thereafter. Progressive local tumor growth occurred for 3 weeks followed by regional lymph node metastases during the fourth week. During local tumor growth, there was a progressive rise in CIC levels (123% rise compared with baseline value; P less than 0.05) which correlated with a fall in both IL-1 and IL-2 generation (r = -0.768). At the time of regional metastasis, the mean CIC levels declined, and there was a further significant decrease in IL production (IL-1 = 0.9% and IL-2 = 10% of controls in tumor bearers). These results show that progressive tumor growth results in decreased IL production by host PBC, and suggest that CIC may be involved in regulating IL generation.

Adenocarcinoma↗

PubMed1983

Circulating immune complexes in patients with colorectal cancer.

We have attempted to better define host humoral immune response in neoplasia by quantitating serial circulating immune complex values before and after surgery in patients with primary or metastatic colorectal cancer. Circulating immune complex levels were correlated with serial carcinoembryonic antigen values and tumor courses in patients with primary resectable colorectal cancer (four patients), resectable liver metastases (three patients), diffuse liver metastases treated with regional chemotherapy (three patients), and untreated intrahepatic (one patient) and extrahepatic metastases (one patient). Circulating immune complex levels, as measured by an antigen-nonspecific assay, which utilized 4 percent polyethylene glycol insolubilization, were increased in all patients at presentation (734 delta OD450 +/- 381) when compared with normal human control sera (202 +/- 4, p less than 0.05). No particular relation was found between presenting circulating immune complex levels and tumor burden. Progressive circulating immune complex increases were demonstrated only in patients whose tumors were either completely removed or dramatically responded to regional therapy (that is, when the tumor antigen load, as reflected by the carcinoembryonic antigen value, rapidly diminished). Serum samples obtained at times of presumed antibody excess in the patients with gastrointestinal cancers were found to contain unexpectedly high concentrations of IgA. We believe these data demonstrate the kinetics of circulating immune complex change during tumor course and they have allowed us to begin to identify circulating immune complex components in patients with colorectal cancer. The results confirm our earlier findings in patients with gestational tumors and differ from accepted relations between immune complexes and tumor growth.

Antigen-Antibody Complex↗

PubMed1982

An evaluation of two antigen nonspecific assays for circulating immune complexes using a model system.

Two methods of detecting circulating immune complexes (CIC) in serum, the Protein A-glass fiber filter assay (PA-GFF) and the polyethylene glycol (PEG) insolubilization assay, were compared using a model system of BSA/anti-BSA. Supernatants of the quantitative precipitin curve from extreme antigen excess through antibody excess were tested by both methods. The PEG assay detected soluble CIC in all areas where expected by comparison with the Farr Test; the filter assay did not, although it did detect aggregated globulins quantitatively. The PEG assay detected high levels of CIC in serum of rheumatoid arthritis patients and low levels in normal human serum. Postprandial samples and plasma with heparin or EDTA caused unpredictable increases in results in the PEG assay so that for best results the PEG assay should be run on serum from fasting individuals. PEG insolubilized complexes were analyzed and found to contain expected serum components. A slight modification of the original method was made and tested using two other model complex systems and known CIC-containing sera. The PEG turbidity assay it fast, easy, reproducible, and suitable for quantitating and isolating immune complexes in serum.

Animals↗

PubMed1979

Inhibition of the interaction between the complement component Clq and immune complexes.

Several groups of compounds were examined for their ability to inhibit in vitro the binding of Clq to insoluble immune complexes. As expected from previous studies, polyinosinic acid, liquoid, sodium pentosan polysulfate, aliphatic diamines and heparin are good inhibitors. This study shows that compounds with much lower toxicity, such as certain amino acids and substances with vitamin B6 activity (pyridoxal-5-phosphate:P5P) were also capable of decreasing the binding of Clq. Using methods of equilibrium dialysis and difference spectra, it was shown that this compound binds to both, Clq und IgG antibody by forming Schiff bases. Clq binds approximately 10 times more P5P when compared to IgG. Immune complexes prepared with IgG antibody modified by P5P and stabilized with sodium borohydride had the same complement-fixing and Clq-binding capacity as normal immune complexes. This suggests that the inhibition of Clq-binding to immune complexes by P5P is due to a modification of lysyl resides in Clq. Collagen and IgG fragments derived from Fc were also found to inhibit Clq binding to immune complexes, but at higher concentrations than the above small-molecular compounds and with a different mode of action.

Animals↗

PubMed1978

Activation of the classical and alternative pathways of complement fixation by immune complexes containing normal and tryptophan-modified immunoglobulin G.

Koshland's reagent (2-hydroxy-5-nitrobenzyl bromide (NBB)) has been shown to modify tryptophanyl residues in anti-ovalbumin IgG. As little as 2 moles NBB/mole IgG antibody are sufficient to block the classical pathway of complement activation when the antibody is complexed to antigen (ovalbumin). In contrast, immune complexes containing antibody with the same degree of tryptophanyl substitution will activate the alternative pathway of complement fixation. Immune complexes containing F(ab')2 fragments derived from anti-ovalbumin IgG do not activate the classical pathway. When measuring the percentage activation of C3 using the method of Laurell, NBB does not affect the alternative pathway of the complement system up to a molar ratio of 2 NBB/F(ab')2. The above findings, provide a means to evaluate the relative contribution of complement activation by the different pathways.

Animals↗