Biomedical subjects

F D Finkelman

Publications and source records attributed to F D Finkelman.

At least 127 records · Page 7Linked to original sources

PubMed1991

Heligmosomoides polygyrus: CD4+ but not CD8+ T cells regulate the IgE response and protective immunity in mice.

Oral inoculation of BALB/c mice with infective larvae of Heligmosomoides polygyrus resulted in chronic infection characterized by the release of parasite eggs in the feces for several months. The actual number of eggs per gram of feces was dependent on the dose of the inoculum. Serum IgE in infected mice peaked at a level of greater than 70 micrograms/ml during Weeks 3 through 6 following inoculation, and high levels of IgE (greater than 40 micrograms/ml) persisted for over 14 weeks. Protective immune responses resulted in reduced egg production and the development of markedly fewer adult worms in the small intestines following a challenge inoculation. The role of CD4+ and CD8+ T cells in these responses was examined by depletion in vivo of either T cell subpopulation with rat mAb specific for the appropriate determinants. Mice treated with anti-CD4 during a primary infection had increased EPG which was due primarily to an increase in worm fecundity (eggs produced per adult female). A challenge inoculation of mice that had been cleared of the primary infection with an anthelmintic drug induced a protective response that reduced development of new adult worms by 70-80% and their fecundity by greater than 90%. This protective response was abrogated by injection of mice with anti-CD4. Serum IgE diminished when adult worms were removed after anthelmintic treatment. A more precipitous drop in serum IgE followed successive treatments of mice with an anthelmintic and anti-CD4. In addition, the anamnestic serum IgE response to a challenge inoculation was reduced by over 80% in anti-CD4-treated mice. Anti-CD8 treatment had no appreciable effect on the immunological or parasitological parameters measured following a challenge inoculation with H. polygyrus. Thus, CD4+ T cells regulate host protective immunity, worm fecundity, and IgE levels in an H. polygyrus infection. This experimental system may be particularly suitable for analysis of chronic nematode infections of humans and livestock because of the responsiveness of the parasite in vivo to changes in host immune function.

Animals↗

PubMed1991

Analysis of immunoglobulin heavy chain delta transcription termination in the production of delta S or delta M mRNA.

mRNA encoding secreted immunoglobulin is synthesized either by termination of transcription 3' to secreted terminus sequences and 5' to the membrane terminus sequences or by cleavage of a pre-mRNA transcript containing both secreted and membrane sequences at the appropriate polyadenylation site 5' to the membrane sequences. In vitro "run-on" transcription analysis was used to examine the delta transcription termination patterns in resting membrane IgD expressing B lymphocytes, in KWD2, an IgD-secreting hybridoma, and in TEPC 1017, an IgD-secreting plasmacytoma. In resting B cells, transcription terminated in a region 4 to 7 kilobases 3' to the delta M exons. Transcription in the secreting cells continued through the delta M exons, but terminated at more upstream sites. Additionally, an increased loading of polymerases in the region of the delta S exon and its 5' flanking sequence was detected in the secreting cells and was particularly pronounced in TEPC 1017. It is hypothesized that this peak correlates with high delta S mRNA production.

Amanitins↗

PubMed1991

Regulation and biological function of helminth-induced cytokine responses.

The immunological hallmarks of infection with parasitic helminths, namely eosinophilia, mastocytosis and increased IgE synthesis, all appear to be induced by cytokines from the TH2 subset of CD4+ T cells: IgE production is stimulated by interleukin 4 (IL-4), eosinophilia by IL-5 and mastocytosis by IL-3 and IL-4. Here, Fred Finkelman and colleagues argue that the functional significance of the eosinophilia-mastocytosis-IgE axis in helminth infection is unclear and suggest that in some worm infections TH2-cell cytokines may contribute to host protection, while in others they may promote parasite survival.

Animals↗

PubMed1991

Regulation of murine in vivo IgG and IgE responses by a monoclonal anti-IL-4 receptor antibody.

Although the cytokine interleukin 4 (IL-4) stimulates LPS-activated mouse B lymphocytes to secrete both IgG1 and IgE, an anti-IL-4 antibody completely inhibits IgE responses but has little or no effect on several in vivo IgG responses. IL-4 might, therefore, have a restricted role in the generation of in vivo humoral immune responses. Alternatively, IgG1 responses might be stimulated by IL-4 secreted by T cells that are interacting directly with B cells, so that anti-IL-4 antibody cannot neutralize IL-4 before it binds to a B cell IL-4 receptor. In contrast, an antibody that blocks the IL-4 receptor (IL-4R) should equally inhibit responses to IL-4 produced proximal to or distant from a B cell. This reasoning led us to determine the ability of an anti-IL-4R mAb to affect antibody production in mice injected with a goat antibody to mouse IgD (GaM delta) or inoculated with the nematode parasite Heligmosomoides polygyrus. Anti-IL-4R mAb, like anti-IL-4 mAb, blocked IgE responses by greater than 95% and enhanced IgG2a responses to a variable extent. Anti-IL-4R mAb, however, had only a modest and variable inhibitory effect on the induction of IgG1 responses, although it caused these responses to terminate more rapidly. A combination of anti-IL-4 and anti-IL-4R mAbs totally blocked goat anti-mouse IgD antibody (GaM delta)-induced IgE production but had no additive inhibitory effect on IgG1 production. These observations are most consistent with the view that IL-4 is required for a primary IgE response, but has relatively little role in the induction of IgG1 responses in the in vivo systems studied.

Animals↗

PubMed1991

Induction of Ly-6A/E expression by murine lymphocytes after in vivo immunization is strictly dependent upon the action of IFN-alpha/beta and/or IFN-gamma.

Ly-6A/E is a phosphatidylinositol-linked membrane protein which mediates murine T and B cell signalling. IFN-gamma, IFB-alpha/beta, LPS, and IL-4 have all been reported to induce or upregulate Ly-6A/E by normal lymphocytes. Since no systematic study has addressed the stimulant selectivity of Ly-6A/E expression by murine lymphocytes nor investigated its induction and regulation during primary in vivo immune responses we analyzed in vitro Ly-6A/E expression after murine stimuli and during a number of distinct in vivo immunizations. We show that LPS induces B cell Ly-6A/E in vitro by stimulating the release of IFN-alpha/beta by 'contaminating' adherent cells. In the presence of anti-IFN-gamma + anti-IFN-alpha/beta antibodies, no Ly-6A/E was induced upon addition of multiple cytokines, including IL-4, or mitogenic doses of anti-Ig antibody. Furthermore, IFN-gamma-containing, CD4+ T cell (Th1) supernatants potently induced Ly-6A/E by murine B cells whereas IL-4-containing (Th2) supernatants were either weak or ineffective; anti-IFN-gamma + anti-IFN-alpha/beta inhibited Ly-6A/E induction by both Th1 and Th2 supernatants. Immunization of mice with Brucella abortus or poly (I).poly (C) resulted in induction of Ly-6A/E expression by virtually all B and T cells, whereas injection of G alpha M delta led to peak induction of Ly-6A/E by approximately 50% of both B and T cells. Lymphocytes from mice infected with the nematode parasites Nippostrongylus brasiliensis or Heligmosomoides polygyrus expressed no Ly-6A/E.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion.

Plasma cells secrete immunoglobulins other than immunoglobulin M (IgM) after a deletion and recombination in which a portion of the immunoglobulin heavy-chain locus (IgH), from the 5'-flanking region of the mu constant-region gene (C mu) to the 5'-flanking region of the secreted heavy-chain constant-region gene (CH), is deleted. The recombination step is believed to be targeted via switch regions, stretches of repetitive DNA which lie in the 5' flank of all CH genes except delta. Although serum levels of IgD are very low, particularly in the mouse, IgD-secreting plasmacytomas of BALB/c and C57BL/6 mice are known. In an earlier study of two BALB/c IgD-secreting hybridomas, we reported that both had deleted the C mu gene, and we concluded that this deletion was common in the normal generation of IgD-secreting cells. To learn how such switch recombinations occur in the absence of a switch region upstream of the C delta 1 exon, we isolated seven more BALB/c and two C57BL/6 IgD-secreting hybridomas. We determined the DNA sequences of the switch recombination junctions in eight of these hybridomas as well as that of the C57BL/6 hybridoma B1-8. delta 1 and of the BALB/c, IgD-secreting plasmacytoma TEPC 1033. All of the lines had deleted the C mu gene, and three had deleted the C delta 1 exon in the switch recombination event. The delta switch recombination junction sequences were similar to those of published productive switch recombinations occurring 5' to other heavy-chain genes, suggesting that nonhomologous, illegitimate recombination is utilized whenever the heavy-chain switch region is involved in recombination.

Animals↗

PubMed1991

Production of interleukin-4 and other cytokines following stimulation of mast cell lines and in vivo mast cells/basophils.

Interleukin-3 (IL-3)-dependent mast cell lines, upon stimulation by calcium ionophores or by Fc epsilon RI cross-linking, express mRNA for, and secrete, a distinct pattern of cytokines, similar to those secreted by cloned mouse T cells of the TH2 type. The mast-cell-derived cytokines include IL-3, IL-4, IL-5 and IL-6. Not only in vitro mast cell lines, but also in vivo derived peritoneal mast cells secrete cytokines. An in vivo derived cell, in mouse spleen and bone marrow, secretes IL-4 and other cytokines upon stimulation with calcium ionophores or by Fc epsilon RI cross-linking or Fc gamma RII cross-linking. The IL-4-producing cells are highly enriched in the Fc epsilon R+ subset of spleen and bone marrow cells. These Fc epsilon R+ cells produce large amounts of IL-4, and they have characteristics similar to those of immature mast cells and/or basophils. It is possible that cytokines produced by mast cells and/or basophils participate in allergic inflammatory diseases.

Animals↗

PubMed1991

Differences in the expression of the cardiopulmonary alterations associated with anti-immunoglobulin E-induced or active anaphylaxis in mast cell-deficient and normal mice. Mast cells are not required for the cardiopulmonary changes associated with certain fatal anaphylactic responses.

We compared the changes in heart rate (HR), pulmonary dynamic compliance (Cdyn), and pulmonary conductance (GL) associated with three different models of anaphylaxis in genetically mast cell-deficient WBB6F1-W/Wv and congenic normal (+/+) mice. Intravenous infusion of a monoclonal rat anti-mouse IgE produced a marked tachycardia, diminutions in Cdyn and GL, and death in +/+ but not W/Wv mice, and +/+ mice sensitized to develop high circulating levels of IgE exhibited HR, Cdyn, and GL responses to rat anti-IgE challenge which were significantly less intense than those in nonimmunized +/+ mice. By contrast, virtually identical cardiopulmonary responses were observed in either +/+ or W/Wv mice challenged to elicit pure active anaphylactic responses or simultaneous active and anti-IgE-dependent anaphylaxis. These findings show that anaphylactic responses associated with significant tachycardia, reductions in Cdyn and GL, and death can occur in the virtual absence of tissue mast cells. This is true even though, in normal mice, such responses are associated with extensive degranulation of tissue mast cells. By contrast, certain models of anaphylaxis, such as that induced in nonsensitized mice by anti-mouse IgE, can not be elicited in the absence of mast cells.

Anaphylaxis↗

PubMed1990

Rapid loss of IgM expression by normal murine B cells undergoing IgG1 and IgE class switching after in vivo immunization.

Injection of mice with polyclonal goat anti-mouse IgD antibody (G alpha M delta) stimulates a potent T cell-dependent immune response characterized by large increases in serum IgG1 and IgE concentrations and by the generation of substantial numbers of membrane (m)IgG1+ B cells. The onset of this response occurs 6 days after G alpha M delta injection and peaks by day 7 to 8. Utilizing two color fluorescence analysis and cell sorting we demonstrate that most mIgG1-expressing B cells lack mIgM during the period of onset of Ig isotype switching (day 6). Both IgG1 and IgE are produced predominantly by mIgM- cells. On day 6, IgG1 and IgE are secreted predominantly by cells expressing mIgG1 and mIgE, respectively. By day 8, a majority of the IgG1 secretion occurs among the mIgG1- cells but virtually all IgE secretion continues to come from the mIgE+ population. B cells that strongly express mIgG1 secrete little IgM or IgE. Freshly harvested B cells expressing mIgG1, 6 days after G alpha M delta injection, have undergone substantial deletion of CH mu-specific DNA in contrast to their mIgG1- counterparts. Hence, the great majority of B cells that switch to the IgG1 or IgE isotypes in vivo rapidly lose their expression of IgM.

Animals↗

PubMed1990

Polyclonal activation of the murine immune system by an antibody to IgD. X. Evidence that the precursors of IgG1-secreting cells are newly generated membrane IgD+B cells rather than the B cells that are initially activated by anti-IgD antibody.

Injection of BALB/c mice with an affinity-purified goat antibody to mouse IgD (GaM delta) stimulates T cell-independent B cell activation as well as later T cell activation. Activated T cells then induce polyclonal differentiation of B cells into IgG1-secreting cells, which results in an approximately 100-fold increase in serum IgG1 level. It is not known whether the same B cells that are initially activated by GaM delta are the progenitors of the IgG1-secreting cells. To investigate this issue a system was developed in which CB20 mice, which are congenic to BALB/c mice but express Ig of the beta allotype rather than the BALB/c alpha allotype, were injected with GaM delta and simultaneously or subsequently also received BALB/c B cells. The IgG1 response generated by the donor BALB/c B cells was quantitated by an assay specific for IgG1 of the alpha allotype. Our experiments with this system indicate that: 1) BALB/c B cells transferred 2 days after CB20 mice were injected with GaM delta generate a much larger IgG1 response than do BALB/c B cells transferred simultaneously with GaM delta antibody; 2) B cells that express membrane IgD generate the great majority of this response; 3) differences in the magnitudes of the responses of BALB/c B cells transferred at different times after CB20 mice were injected with GaM delta antibody cannot be explained by differences in homing of the donor B cells to the host spleen or by short survival of donor BALB/c B cells after their transfer; and 4) the response made by donor BALB/c B cells transferred 2 days after CB20 mice were injected with GaM delta is proportionate to donor cell representation in the host spleen 1 day after their transfer, whereas the response made by donor cells transferred simultaneously with GaM delta is disproportionately small. These observations suggest that most of the IgG1 antibody made by GaM delta-injected mice is generated by newly produced, mIgD+ B cells that appear approximately 2 days after GaM delta injection, rather than by those B cells that are present in the spleen at the time of GaM delta injection, and support the view that signals that induce B cell secretion of Ig require an interaction with at least partially activated Th cells.

Animals↗

PubMed1990

Rapid stimulation of large specific antibody responses with conjugates of antigen and anti-IgD antibody.

Injection of mice with goat anti-mouse IgD antibody stimulates a large IgG1 anti-goat IgG antibody response, as well as polyclonal IgG1 production. To determine if this phenomenon could be used to induce large antibody responses to other Ag, covalent conjugates were produced between BSA or other Ag and H delta a/1, a mAb specific for IgD of the a allotype, and between BSA and AF3.33, a mAb specific for IgD of the b allotype. Injection of H delta a/1-BSA into BALB/c mice, which express Ig of the a allotype, or into (BALB/c x CB20)F1 mice (a x b allotype heterozygotes) induced IgG1 anti-BSA antibody responses that peaked 8 to 9 days after injection, and were more than 1000 times larger than those induced by injection of BSA alone, and 100 times larger than those induced by injecting unconjugated BSA plus H delta a/1. H delta a/1-BSA was no more immunogenic than unconjugated BSA when injected into CB20 mice, which express Ig of the b allotype, while AF3.33-BSA greatly enhanced anti-BSA antibody production in CB20, but not in BALB/c mice. Mice serially immunized with three different Ag conjugated to H delta a/1 made large antibody responses to all three Ag, provided that the mouse strain used did not recognize allotypic determinants on H delta a/1 as foreign and produce a neutralizing antibody response. Intravenous and s.c. routes of inoculation produced responses of similar magnitude and relatively low variability; responses to footpad or intramuscular inoculation were more variable, and i.p. inoculation induced smaller responses. Injection of BALB/c mice i.v. with 100 micrograms of H delta a/1-BSA induced an IgG1 anti-BSA response of 5.6 mg/ml, which was approximately 70% of the total IgG1 response. Anti-BSA responses to 30 micrograms of conjugate or less were much smaller, but could be considerably enhanced by adding unconjugated H delta a/1 to the inoculum. This system will be useful for the rapid stimulation of large antibody responses to biologically important Ag, and for investigating mechanisms of Ag processing and B and T cell activation.

Animals↗

PubMed1990

IL-3 promotes production of IL-4 by splenic non-B, non-T cells in response to Fc receptor cross-linkage.

A spleen cell population that lacks CD3, CD4, CD8, Thy-1, B220, and class II major histocompatibility complex cell-surface markers (non-B, non-T cells) produces IL-4 when cultured in wells coated with IgE. Their production of IL-4 in response to plate-bound (PB)-IgE is strikingly enhanced by IL-3, and in the presence of IL-3, these cells also produce IL-4 in response to PB-IgG2a. The effect of IL-3 is not mimicked by IL-1, IL-2, IL-5, IL-6, IL-7, granulocyte-macrophage CSF (GM-CSF) or IFN-gamma. Non-B, non-T cells cultured with IL-3 for 12 h acquire the capacity to produce enhanced amounts of IL-4 in response to subsequent culture with PB-Ig even if IL-3 is omitted from the second culture. Irradiated cells also respond to IL-3 with enhanced capacity to produce IL-4 to PB-Ig, indicating that cell proliferation is not required for the effect of IL-3. The IL-3 effect can be obtained in vivo; treatment of mice with a total dose 90,000 U of synthetic IL-3 over a 3-day period results in the presence of splenic and peritoneal cavity non-B, non-T cells that produce enhanced amounts of IL-4 in response to PB-Ig. The FcR that mediates the response to PB-IgE appears to be Fc epsilon RI because cells can be sensitized with IgE anti-DNP mAb, washed, cultured for 15 h at 37 degrees C, washed again, and stimulated to produce IL-4 with 0.1 to 1 ng/ml of TNP10-OVA. IL-3 does not appear to mediate its function by increasing the number of Fc epsilon RI because it can exert its effect when cultured with non-B, non-T cells after they have been sensitized with IgE anti-DNP. However, IL-3 pretreatment does affect the signaling process in that non-B, non-T cells sensitized with IgE anti-DNP show strikingly reduced production of IL-4 to concentrations of TNP10-OVA of 100 ng/ml or more whereas cells pretreated with IL-3 show little or no diminution in IL-4 production at concentrations of TNP10-OVA up to 1 microgram/ml.

Animals↗

PubMed1990

Anti-CD3 antibody induces rapid expression of cytokine genes in vivo.

Anti-CD3 antibody was administered to mice i.v. and the kinetics of spleen cell cytokine mRNA expression studied by Northern analysis. Untreated mice and mice receiving control antibody had low or undetectable amounts of mRNA for c-fos, c-myc, IL-2, IL-4, and IFN-gamma. After injection of anti-CD3 antibody, substantial increases in all were found. Induction of c-fos was detected at 10 min and of c-myc at 30 min after injection. IL-2, IL-4, and IFN-gamma mRNA were induced by 30 min and reached peak levels at 60 min. Thereafter, IL-2 and IL-4 mRNA declined, whereas IFN-gamma mRNA persisted. The induced cytokine mRNA was not observed in athymic nu/nu mice nor in normal spleen cells from which T cells had been depleted in vitro. The early in vivo induction of IL-4 mRNA contrasts with prior in vitro studies in which IL-4 production was difficult to detect after primary stimulation. To assess the possibility that many T cells had been preprimed in vivo, germfree mice were compared with conventional mice and no differences in cytokine mRNA were found. These data show that T cell-dependent IL message production can be induced rapidly in vivo without prepriming and that the cytokine messages induced after anti-CD3 antibody administration do not suggest a predominance of either Th1 or Th2 type cells.

Animals↗

PubMed1990

Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells.

T cell populations derived from naive mice produce very small amounts of interleukin 4 (IL-4) in response to stimulation on anti-CD3-coated dishes. IL-4 production by such cells is mainly found among large- and intermediate-sized T cells and is dependent upon IL-2. Injection of anti-IgD into mice, a stimulus that leads to striking increases in serum levels of IgG1 and IgE, causes a striking increase in the IL-4-producing capacity of T cells. This increase is first observed 4 d after injection of anti-IgD. IL-4 production by T cells from anti-IgD-injected donors is mainly found among large- and intermediate-sized T cells. Small, dense T cells are poor producers of IL-4. The capacity of T cells from anti-IgD-injected donors to produce IL-4 is enhanced by addition of IL-2 and is largely, but not completely, inhibited by neutralization of in situ produced IL-2. These results indicate that the control of IL-4 production in T cells from naive and anti-IgD-injected donors is similar. However, it is possible that a portion of the IL-4-producing activity of T cells from activated donors is IL-2 independent. Although small T cells from naive donors have a very limited capacity to produce IL-4 in response to stimulation with anti-CD3, even in the presence of added IL-2, they can give rise to IL-4-producing cells upon in vitro culture on plates coated with anti-CD3 if both IL-2 and IL-4 are added. This leads to the appearance of IL-4-producing cells within 2 d. When analyzed after 5 d of culture by harvesting and re-exposure to anti-CD3-coated culture wells and IL-2, these cells have increased their IL-4-producing capacity by approximately 100-fold. The development of IL-4-producing cells in response to anti-CD3, IL-2, and IL-4 is not inhibited by interferon gamma (IFN-gamma), nor does IFN-gamma diminish IL-4 production by these cells upon challenge with anti-CD3 plus IL-2.

Animals↗

PubMed1990

The in vivo generation of murine IgD-secreting cells is accompanied by deletion of the C mu gene and occasional deletion of the gene for the C delta 1 domain.

Mature, resting rodent, and primate B lymphocytes express two membrane Ig isotypes, IgM and IgD. Although membrane IgD production by these cells is regulated at a transcriptional level, and does not require deletion of the C mu gene, C mu has been deleted in all of the IgD-secreting tumor cells that have been studied. These IgD-secreting tumors, which include two mineral oil-induced plasmacytomas and three IgD-switch variants of an IgM-secreting hybridoma, might not, however, be representative of the rare IgD-secreting cells generated in response to an immune stimulus. A recent study of mice injected with a goat antibody to mouse IgD has demonstrated the generation of a relatively large secretory IgD response in these animals. We have now produced hybridomas by fusing spleen cells from these mice with a non-Ig-secreting plasmacytoma. Two of these hybridomas, KWD-1 and KWD-2, secrete IgD and express cell membrane IgD. Both of these hybridomas were found to have deleted the C mu gene. KWD-2 produces a delta-chain mRNA and a delta-chain protein similar in size to those previously reported for normal secreted mouse IgD; however, KWD-1 synthesizes a secretory delta-chain mRNA that is approximately 0.25 kb smaller than the KWD-2 secretory delta-chain mRNA and secretes IgD with a delta-chain that is approximately 21 kDa smaller than the secretory delta-chain of KWD-2. ELISA studies with epitope-defined anti-delta mAb indicate that KWD-2 has both delta Fc (C delta 3) [corrected] and delta Fd (C delta 1) [corrected] determinants, whereas KWD-1 has delta Fc but not delta Fd. These studies also demonstrate that the Ag-binding site of KWD-1 is not deleted because KWD-1 specifically binds goat IgG. Northern blot analyses with exon-specific probes indicate that while both KWD-1 and KWD-2 synthesize kappa-chain mRNA and delta-chain mRNA that includes the VH, C delta hinge, and C delta 3 exons, the C delta 1 exon is present only on the KWD-2 delta-chain mRNA. Southern blot analysis confirms that the C delta 1 exon has been deleted in KWD-1, but not KWD-2. We have previously noted that a secretory delta-chain mRNA that is similar in size to that produced by KWD-1 accounts for approximately 25% of the splenic secretory delta-chain mRNA produced by goat anti-mouse IgD antibody-injected mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1990

IL-4 production by T cells from naive donors. IL-2 is required for IL-4 production.

Utilizing a sensitive and selective assay for IL-4, it was shown that lymph node T cells from naive mice could produce small amounts of this lymphokine in response to anti-CD3 antibodies adsorbed to culture dishes. The capacity of these cells to produce IL-4 in response to plate-bound anti-CD3 was substantially enhanced by the addition of IL-2 to the culture and was strikingly inhibited by monoclonal anti-IL-2 antibody. Thus, IL-2 appears to be essential for IL-4 production by anti-CD3 antibody-stimulated T cells from naive mice. The effect of IL-2 was not mediated either by preferential proliferation or survival of precursors of IL-4 producing cells, indicating that IL-2 regulates T cell production of IL-4. IL-4 producing capacity of T cells from naive mice was found mainly among CD4+ T cells. Large T cells produced much more IL-4, on a per cell basis, than did small T cells. In contrast, small T cells appeared to be equal or superior to large T cells in producing IL-2. The superiority of large T cells in IL-4-producing capacity was not accounted for by a lack of an accessory cell population from the small T cells as addition of large spleen cells depleted of both B and T cells did not enhance IL-4 production by small lymph node T cells. These results suggest that the bulk of IL-4 production by T cell populations, from normal mice, in response to anti-CD3 depends upon cells that are already activated and that IL-2 is required for such production.

Animals↗

PubMed1990

Infection with Nippostrongylus brasiliensis or injection of anti-IgD antibodies markedly enhances Fc-receptor-mediated interleukin 4 production by non-B, non-T cells.

Non-B, non-T cells from spleen and bone marrow of naive mice produce IL-4 upon stimulation by plate-bound IgE or IgG2a in the presence of IL-3. Infection of mice with Nippostrongylus brasiliensis (Nb) or injection of anti-IgD antibodies, treatments known to cause striking polyclonal IgE responses, increase the number of splenic non-B, non-T cells and cause 10-30-fold increase in IL-4 production by a standard number of these cells. In Nb-infected mice, IL-4 producing non-B, non-T cells can be found in the lungs, a site through which Nb larvae migrate. Non-B, non-T cells from anti-IgD-injected mice produce IL-4 in response to anti-IgE antibodies, indicating that these cells have been sensitized in vivo with IgE and that crosslinkage of such IgE can lead to stimulation of lymphokine production. Similarly, non-B, non-T cells from Nb-infected mice produce IL-4 upon stimulation with Nb-antigen, indicating that antigen can also crosslink receptors on in vivo sensitized non-B, non-T cells and stimulate lymphokine production. The striking increases in the IL-4-producing capacity of the splenic non-B, non-T cell population in anti-IgD-injected and Nb-infected mice and the in vivo sensitization of these cells strongly suggests that they may have an important role in lymphokine production in helminthic infections and other situations marked by striking elevations of serum IgE levels.

Animals↗

PubMed1990

Evaluation of ricin A chain-containing immunotoxins directed against different epitopes on the delta-chain of cell surface-associated IgD on murine B cells.

Over the past decade, immunotoxins (IT) composed of mAb covalently coupled to toxins or their subunits have been developed for the treatment of malignancies and autoimmune diseases. Despite specific binding to target cells, not every mAb makes a therapeutically potent ricin A chain-containing IT (IT-A). A number of variables influence the potency of a mAb as an IT-A, including the affinity of the mAb, the nature and density of the cell surface Ag, and the type of target cell used. The present report investigates the influence of the epitope specificity of a mAb on the effectiveness of that mAb as an IT-A. Seven mAb directed against different regions of the mouse delta H chain of surface IgD, were conjugated to deglycosylated ricin A chain, and tested for their ability to kill murine B cells. The panel of IT-A had similar A chain activities and similar binding avidities. However, the mAb directed against epitopes in the Fc portion of surface IgD made more effective IT-A than those directed against epitopes in the Fd region. Overall, the anti-Fc-A were approximately 60- to 150-fold more toxic than the anti-Fd-A. Taken together with previous studies, these findings suggest that the epitope on a target Ag recognized by a given mAb is an important variable in determining the potency of a mAb as an IT-A.

Antibodies, Monoclonal↗