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Biomedical subjects

M J Caulfield

Publications and source records attributed to M J Caulfield.

54 records · Page 3Linked to original sources
PubMed1988

Specific antigen/antibody complexes induce the in vivo production of a parallel set of nonantigen-binding idiotype-positive antibodies.

Immune complexes prepared with the polysaccharide antigen (PnC) extracted from Streptococcus pneumoniae R36a and two different PnC-specific antibodies were found to differ in their regulatory properties depending on the isotype of the antibody. Thus, complexes formed in antibody excess with TEPC15 (IgA) were suppressive whereas complexes formed with 96-G (IgG3) antibodies enhanced the IgM response to PnC. During the course of these studies, we found that little or no PnC-specific IgG antibody was induced during the response to PnC coupled to sheep red blood cells (PnC-SRBC). Interestingly, however, immunization with 96-G/PnC complexes either alone or with PnC-SRBC resulted in the induction of IgG3 antibodies that express the T15 idiotype (Id) but which do not bind PnC. This unique IgG3 response occurred after injection of 96-G/PnC complexes formed in antibody excess but not when complexes were formed in antigen excess. The Id+ nonspecific IgG3 response peaked on day 5 and could be activated with 96-G/PnC complexes but not with free PnC antigen. The Id+ nonspecific response was not due to polyclonal activation of IgG3 production since there was no difference in IgG3 levels in mice injected with 96-G/PnC complexes with those injected with PnC-SRBC. Finally, mice that had been suppressed for expression of the T15 Id by neonatal injection of anti-Id antibody were able to produce Id+-unspecific IgG3 antibody after immunization with 96-G/PnC complexes, further suggesting that Id+ IgG3 was produced by different clones than those that usually comprise the antibody response to PnC. The results suggest that the formation of IgG immune complexes during an immune response may result in stimulation of idiotypically related clones thus resulting in degeneracy of the immune response.

Animals↗
PubMed1988

Reappraisal of the role of radical radiotherapy and salvage cystectomy in the treatment of invasive (T2/T3) bladder cancer.

One hundred and eighty-two patients with invasive (T2/T3) bladder cancer were treated by radical radiotherapy at the London Hospital between 1974 and December 1985. Cystectomy was reserved for patients whose tumours either did not respond completely to radiation or recurred later, provided they were fit for surgery and had not developed distant metastases. The overall corrected 5-year survival rate was 40%; 75 patients responded to radiation and did not relapse during the period of follow-up; 20 patients had an initial response to radiation but subsequently relapsed, with a 5-year survival rate following relapse of 20%. Of these, 11 patients had a cystectomy with a 5-year survival following relapse of 36%, whereas all 9 patients who did not have a cystectomy died within 3 years; 87 patients who did not respond to radiation had a 5-year survival rate of 18%. Of these, 22 patients underwent salvage cystectomy with a 5-year survival of 47%, whereas the 65 patients who did not have a cystectomy had a 5-year survival of 3%. These results justify a policy of radical radiotherapy and salvage cystectomy rather than elective cystectomy in the treatment of invasive bladder cancer.

Adult↗
PubMed1988

Detection of bacteria in the presence of antibiotics by using specific monoclonal antibodies to neutralize the antibiotics.

Inactivation of penicillin and gentamicin in cultures was achieved by using monoclonal antibodies against these antibiotics. A viridans group streptococcus (penicillin MIC, less than or equal to 0.06 micrograms/ml) and Escherichia coli ATCC 35218 (gentamicin MIC, less than or equal to 1 microgram/ml) were able to grow in broth containing 0.25 micrograms of penicillin per ml and 4 micrograms of gentamicin per ml, respectively, when the specific antibodies were added. This procedure may be useful to increase the yield of bacteria from body fluid specimens that contain antibiotics.

Anti-Bacterial Agents↗
PubMed1988

Decreased pathogenicity of murine leukemia virus-Moloney in gnotobiotic mice.

Newborn germ-free (GF) and conventional (CV) BALB/c mice were infected with murine leukemia virus-Moloney (MuLV-M) and subsequently monitored for virus expression and leukemia development. GF mice expressed more than 10-fold less virus in peripheral blood compared with CV mice, despite equivalent numbers of infected cells in the spleens, lymph nodes, thymi, and bone marrow of both groups. In addition to lower levels of virus expression, the latency period before the onset of fatal leukemias was greatly extended in GF mice; the first and last fatalities were recorded at 25 and 43 weeks postinfection, respectively, with a mean survival time of approximately 36 weeks. In CV mice, the first and last fatalities occurred at 8 and 17 weeks, respectively, with a mean survival time of approximately 13.5 weeks. Finally, the gross pathology of involved lymphoid organs varied in the two groups. GF mice experienced severe splenomegaly with or without lymphadenopathy but without thymoma; CV mice, in contrast, developed splenomegaly, lymphadenopathy, and severe thymoma. Collectively, these results indicate a marked resistance of GF animals to MuLV-M and suggest that the level of immune system activation may influence the pathogenicity of nontransforming retroviruses.

Animals↗
PubMed1987

Immunoregulation by antigen/antibody complexes. I. Specific immunosuppression induced in vivo with immune complexes formed in antibody excess.

Specific immune complexes, prepared at different ratios of antibody to antigen, were examined for their effects on the antibody response of BALB/c mice to the cell wall polysaccharide antigen (PnC) extracted from Streptococcus pneumonia R36a. Mice immunized with complexes formed in antigen excess developed a PnC-specific antibody response that was equivalent to that in mice injected with free antigen. On the other hand, mice injected with complexes formed in antibody excess developed very little PnC-specific antibody. Furthermore, administration of immune complexes (formed in antibody excess) resulted in suppression of the response to an immunogenic dose of PnC given concurrently or 1 day after injection of immune complexes but not when the antigen was given 1 day before injection of the immune complexes. Injections of free antibody (TEPC-15) also resulted in suppression of the response to antigenic challenge; however, suppression was greatest when the antibody was injected concurrently with the antigen, suggesting that the suppression was mediated through the formation of immune complexes in vivo. The suppression appears to be specific for the antigen (PnC), since in mice injected with TEPC-15/PnC complexes (formed in antibody excess) and challenged with PnC coupled to sheep RBC, only the response to PnC was suppressed.

Animals↗
PubMed1986

The antibody response to specific immune complexes is under genetic control and correlates with the expression of a recurrent idiotype.

The primary antigen-specific antibody response of various strains of mice to TEPC-15/PnC immune complexes has been examined. We found that both BALB/c and C3H mice were good responders to the PnC antigen; however, C3H mice were low responders, whereas BALB/c mice were high responders to the TEPC-15/PnC complexes. Using congenic strains on the C3H and BALB/c background, we have shown that the response to the complexes is not restricted by gene products of the H-2 complex or by the Igh (allotype) locus. However, responsiveness may be controlled by genes linked to the Igh locus, since we have shown that strains that are Ighj, Ighd, and Ighf are low responders, whereas strains that are Igha, Ighb, and Ighe are high responders to the immune complex. Moreover, responsiveness correlates with the expression of the T15 Id as measured using the anti-T15 monoclonal antibody, AB1-2. Thus, strains such as BALB/c, BALB.B, BALB.K, and CB-20, which express high levels of T15 (AB1-2) Id in their PFC response to PnC are relatively high responders to TEPC-15/PnC complexes, whereas C3H, C3H.SW, and C3H-OH, which express low levels of the T15 (AB1-2) Id, are low responders to the complexes. Finally, we found that BALB/c mice are high responders to complexes formed with T15+ antibodies, whereas they are low responders to complexes formed using T15- antibodies. The results suggest that the antigen-specific response to these immune complexes is Id-restricted.

Animals↗
PubMed1985

Idiotype-restricted antibody response to specific immune complexes.

In this report, we compared the immunogenicity of specific antigen/antibody complexes with that of free antigen. The complexes were prepared in antigen excess using the TEPC-15 myeloma protein and a phosphorylcholine-containing polysaccharide antigen (PnC), and the PnC-specific antibody response was measured using a hemolytic plaque assay 5 days after immunization. The results showed that the complexes were as immunogenic as the free antigen; however, the PnC-specific antibody response induced with the complexes was completely dominated by one particular idiotope (defined by plaque inhibition with the AB1-2 monoclonal antibody). On the other hand, the response of mice immunized with free antigen (PnC) was dominated to a lesser degree by the AB1-2 idiotope, and there was a great degree of variability in idiotope expression among individual mice. The results suggest that immunization with antigen/antibody complexes restricts the response to the expression of idiotopes that are present in the immune complex.

Animals↗
PubMed1985

Immunologic mechanisms in the pathogenesis of virus-induced leukemia. IV. Mechanism of target cell recognition by autoreactive thymocytes.

Neonatal infection of mice with Moloney murine leukemia virus (MuLV-M) results in the establishment of a chronic virus-carrier state. Such MuLV-carrier mice exhibit several immunologic abnormalities including generalized immunosuppression and autoimmunity. Previously, we found thymocytes from MuLV-M-carrier mice to be cytotoxic for normal syngeneic and allogeneic fibroblasts but not for xenogeneic (hamster) target cells. However, when the same syngeneic or allogeneic target cells were infected with MuLV-M, they were "spared" from the autoreactivity, leading us to speculate that the MuLV receptor on the target cell membrane was involved in the autoreactivity. To address this question, we tested MuLV-carrier thymocytes for their ability to lyse hamster/mouse-hybrid target cells; some of which possessed chromosome 5 (which codes for the ecotropic MuLV receptor). Of the nine hybrid cell lines initially tested, only the five clones that carried chromosome 5 were killed by the autoreactive thymocytes. In additional experiments, we noted that the cytotoxic reaction was inhibited in the presence of a monoclonal antibody that reacts with an MuLV-M gp70 epitope. The results suggest that the autoreactive cytotoxicity is mediated, at least in part, through the formation of a "bridge" between MuLV budding from the membrane of the thymocytes and the ecotropic MuLV receptor on the target cells.

Animals↗
PubMed1984

A computer program for the evaluation of ELISA data obtained using an automated microtiter plate absorbance reader.

A new computer program is described which calculates titers and antibody concentrations from ELISA data. Optical densities are measured in 96-well microtiter plates using an automated colorimeter and simultaneously fed into a microcomputer. The data can then be arranged and printed in an 8 X 12 format corresponding to the format of a 96-well microtiter plate. The computer program can also compute the titers of samples if the samples are arranged and titrated in one of the suggested formats. In addition, the titers of unknown samples can be automatically compared with the titer of a standard to obtain concentrations. An ELISA designed to measure the concentration of murine antibodies to the cell wall polysaccharide (PnC) extracted from Streptococcus pneumoniae was performed to document the use of the program.

Computers↗
PubMed1983

Induction of idiotype-specific suppressor T cells with antigen/antibody complexes.

The effects of immune complexes on the antibody response of BALB/c mice to Streptococcus pneumoniae R36a (Pn) were investigated. The cell wall polysaccharide (PnC) extracted from Pn was used to form complexes with TEPC-15, a myeloma protein that binds to phosphorylcholine determinants on the PnC. Complexes formed at equivalence were cultured with splenic T cells from BALB/c mice for 2 d, and then the cells were added to fresh BALB/c spleen cell cultures to test their effect on the antibody response to Pn, a response dominated by the T15 idiotype family. The results indicate that TEPC-15/PnC complexes induced potent suppressor T cells (Ts) whereas cells cultured with free antigen or free antibody alone had no effect on the plaque-forming cell response to Pn. The suppression was specific since the response to control antigens such as sheep erythrocytes was unaffected. The suppression appears to be idiotype-specific since the Ts had a relatively weak (and in some cases no) effect on the anti-Pn response of BALB/c mice that had been suppressed for T15 idiotopes by neonatal injection of a monoclonal anti-T15 antibody, MaId 5-4. Furthermore, cells cultured with TEPC-15/PnC complexes were shown to express specific receptors for TEPC-15 idiotopes. The results indicate that antigen/antibody complexes may have important immunoregulatory effects because they are potent inducers of idiotype-specific Ts.

Animals↗
PubMed1983

Endotoxin-induced T lymphocyte proliferation.

The lymphocyte response to endotoxin (LPS) has been attributed largely to the action of this agent as a polyclonal activator of B lymphocytes. In this study we found that a cloned murine interleukin 2-dependent cytotoxic T cell line, CT 6, proliferates in response to LPS, thus providing the first evidence that T cells can be stimulated directly by LPS. The response was dose and time dependent and was blocked by polymyxin B, an inhibitor of LPS-induced mitogenesis. The fact that this is a cloned T cell line, free of other potentially contaminating lymphoid cell types, precludes the possibility that this proliferation is due to contaminating B lymphocytes or is mediated by macrophage-derived products such as interleukin 1. Moreover, highly purified splenic T lymphocyte populations (purified by negative/positive selection or by a rigorous column purification procedure) contain a small subpopulation (approximately 3%) of T cells that proliferate in response to LPS. This population is missing in the endotoxin-hyporesponsive C3H/HeJ mouse. As was observed in the CT 6 line, proliferation of splenic T cells in response to LPS was inhibited by polymyxin B. Furthermore, treatment of LPS-stimulated T cells with anti-T cell antibodies plus complement blocks the uptake of 3H-thymidine by these cultures. Exogenous interleukin 1 failed to stimulate the T cell cultures comparably to LPS and therefore cannot account for the degree of stimulation observed. These findings support and extend previous findings that suggested a role for an endotoxin-sensitive T cell population in the induction of certain responses, such as LPS-induced adjuvanticity of the lymphocyte-dependent LPS induction of macrophage procoagulant activity.

Animals↗
PubMed1980

Regulation of the T 15 idiotype-positive, T-independent immune response to Streptococcus pneumoniae R 36 a (Pn). I. Specific suppressor T cells induced by Pn in vitro are antigen-specific and idiotype-positive.

Normal BALB/c spleen cells incubated for 2 days with Streptococcus pneumoniae R 36 a (Pn) vaccine in vitro acquired the specific ability to inhibit the T-independent anti-Pn response of fresh lymphocytes. The activated suppressor cells were susceptible to cytotoxic treatment with mouse anti-theta serum plus complement, and they inhibited the anti-Pn response of B lymphocytes deprived of T cells. The suppressive effect was eliminated by adsorbtion of cells on dishes coated with the C polysaccharide from Pn, and treatment of the suppressor cells with a rabbit antibody specific for TEPC-15 myeloma protein, in the presence of complement, abolished the suppressive effect. The results indicate that stimulation of lymphocytes with a T-independent antigen in vitro activates suppressor T cells bearing a specific antigen receptor that may express the idiotype(s) characteristic of anti-Pn antibody, and that these cells inhibit the Pn-reactive B cells directly.

Animals↗
PubMed1979

Ozonation of mutagenic and carcinogenic polyaromatic amines and polyaromatic hydrocarbons in water.

The Salmonella-microsome assay for mutagenesis was used to determine the effect of ozone on the mutagenesis of selected carcinogens and mutagens in water. Short periods of ozonation were shown to completely inactivate the mutagenicity of several polyaromatic amine mutagens including acriflavine, proflavine, and beta-naphthylamine. Selected polyaromatic hydrocarbons were also sensitive to ozonation. Kinetic studies revealed that the mutagenicity of benzo(a)pyrene, 3-methylcholanthrene, and 7,12-dimethylbenz(a)anthracene was destroyed after short periods of ozonation. To correlate loss of mutagenicity with loss of carcinogenicity, two polyaromatic hydrocarbons were treated with ozone, extracted from water with hexane, and tested for carcinogenicity in mice. When 7,12-dimethyl-benz(a)anthracene and 3-methyl-cholanthrene were treated with ozone, there was a substantial reduction in carcinogenicity compared to control groups treated with oxygen alone. However, a small number of tumors developed in the group of animals receiving a hexane extract of ozonated 7,12-dimethylbenz(a)anthracene. This activity may be due to breakdown products of 7,12-dimethylbenz(a)anthracene that are not mutagenic.

2-Naphthylamine↗
PubMed1979

Ozonation of mutagenic and carcinogenic alkylating agents, pesticides, aflatoxin B1, and benzidine in water.

The effect of ozonation on the mutagenicity of selected chemicals in water was determined. The use of the Salmonella-microsome assay for mutagensis allowed kinetic studies to be performed on the ozonation of all chemicals tested. The results indicate that the mutagenicity of certain pesticides, including captan and Dexon, was inactivated by short periods of ozonation. The mutagenicity of certain alkylating agents including bis(2-chloroethyl)amine and sodium azide was rapidly inactivated by ozonation while other alkylating agents such as beta-propiolactone, propanesultone, and N-methyl-N'-nitro-N-nitrosoguanidine were unaffected by treatment with ozone. The mutagenicity of aflatoxin B1 was rapidly inactivated by treatment with ozone. Three chemicals were shown to be converted to direct mutagens by ozone treatment. Under certain conditions, dimethylhydrazine could be converted to a mutagen that was stable for 3 weeks. A similar chemical, 2-hydroxyethylhydrazine, was converted to an unstable mutagen that was inactive after 24 hr at room temperature. When benzidine was treated with ozone, there was a transient increase in mutagenicity which was lost after longer treatment with ozone.

Aflatoxins↗
PubMedDate not supplied

Treatment of chronic lymphocytic leukemia with an anti-idiotypic monoclonal antibody.

A monoclonal antibody (H-99) was prepared that reacts specifically with the leukemia cells from a patient with stage IV chronic lymphocytic leukemia of B-cell origin. Escalating doses of the antibody were administered to the patient in two courses of therapy. The first course did not result in any significant change in total lymphocyte count; however, the platelet count (which was initially abnormal) rose steadily during treatment to a level greater than 250,000 per mm3. A second course of treatment was begun approximately three months after the first course, and the protocol was modified to consist of five doses of antibody given over a 10-day period, with the highest dose being 500 mg per day. The second course of treatment did not result in any change in total lymphocyte or platelet levels, and there was no significant toxicity associated with the treatment. The failure to induce an anti-tumor response in the patient was probably related to the large concentration (approximately 400 micrograms/mL) of free serum idiotype in addition to the severely compromised immune system of the patient at the time of treatment.

Antibodies, Monoclonal↗