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Biomedical subjects

F D Finkelman

Publications and source records attributed to F D Finkelman.

At least 91 records · Page 5Linked to original sources
PubMed1993

Critical role of interleukin-2 in the development of acute graft-versus-host disease.

Prior work using the parent-into-F1 model of graft-versus-host disease (GVHD) has shown that production of IL-2 by donor CD4+ T cells is an early, initiating event in either acute or stimulatory forms of GVHD. The aim of the present study was to determine whether acute GVHD could be prevented by blocking the effects of IL-2 in vivo during the first 2 weeks of disease. Acute GVHD was induced in B6D2F1 mice by the injection of C57BL/6 spleen cells i.v. Mice were untreated or received either anti-IL-2 mAb (S4B6) or control mAb at the time of GVHD induction and 1 week later. At 2 weeks, untreated or control mAb treated GVHD mice exhibited findings typical of acute GVHD, i.e. (i) in vitro donor anti-host cytotoxic T lymphocyte (CTL) activity, (ii) significant reductions in both numbers and function of splenic lymphocytes, and (iii) in vitro suppressor cell activity which profoundly blocked IL-2 production by normal syngeneic spleen cells. All of these findings were reversed or significantly inhibited in acute GVHD mice receiving anti-IL-2 treatment. Additionally, anti-IL-2 treated GVHD mice exhibited features previously observed in stimulatory GVHD such as: (i) B cell hyperactivity, (ii) a mild defect in CD4+ T cell production of IL-2 in vitro, and (iii) the ability to induce in co-culture a similar CD4+ cell defect in normal, syngeneic F1 spleen cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

The immunoaugmenting properties of murine IgD reside in its C delta 1 and C delta 3 regions: potential role for IgD-associated glycans.

IgD receptor (IgD-R) bearing CD4+ T cells with immunoaugmenting properties in vivo are induced in mice within 24 h after a single injection of dimeric or aggregated IgD. In the present study, we sought to identify the region(s) of IgD responsible for upregulation of IgD-R and for the immunoaugmenting effect of IgD. IgD-R can be upregulated on CD4+ T cells in vitro and in vivo by glutaraldehyde-aggregated mutant IgD or by fragments of enzymatically digested IgD molecules possessing either the C delta 1 domain (Fd delta) or the C delta 3 domain (Fc delta). Neoglycoproteins (D-galactose--BSA and N-acetyl-D-glucosamine--BSA), can competitively block upregulation of IgD-R by IgD in vitro. Furthermore, when injected 1 day before antigen, the aggregated IgD derived molecules, KWD1 (which lacks C delta 1), KWD6 (which lacks C delta 1 plus C delta-hinge), and Fab delta can all cause augmentation of antigen-specific primary and secondary antibody responses comparable to that achieved with intact aggregated IgD. Moreover, the immunoaugmenting effect of intact oligomeric IgD molecules in primary antibody responses is competitively blocked by simultaneous injection of monomeric forms of KWD6 and Fab delta. These results suggest that the binding of IgD to IgD-R, previously shown to be dependent on N-glycans present on Fd delta and Fc delta regions, also contributes to the upregulation of IgD-R and immunoagumentation.

Adjuvants, Immunologic↗
PubMed1993

Brucella abortus induces a novel cytokine gene expression pattern characterized by elevated IL-10 and IFN-gamma in CD4+ T cells.

Immunization of BALB/c mice with killed Brucella abortus (BA) has previously been shown to increase serum IgG2a levels and long-term T cell clones from these mice secrete Th1-associated cytokines: IFN-gamma and IL-2 but not IL-4 or IL-5. We analyzed cytokine gene expression following primary immunization with BA to determine when CD4+ T cells first express cytokine genes and whether specific hypothesized cytokine patterns (e.g. Th precursor, Th0) could be identified prior to a Th1-like pattern. Our results demonstrated a highly consistent and novel pattern of Th1/Th2 cytokine gene expression characterized by elevated IL-10 and IFN-gamma in CD4+ T cells which rapidly manifests itself and is sustained for at least 10 days after immunization. No elevation in IL-2 cytokine gene expression was observed and treatment of BA-immunized mice with blocking anti-IL-2 antibodies had no effect on the cytokine gene expression pattern, although treatment with anti-IFN antibodies resulted in increased IL-4, IL-5, and IL-9 cytokine gene expression, in the absence of any change in IFN-gamma or IL-10 as early as 4 days after immunization. These results suggest that a whole pathogen may trigger sufficient costimulatory signals to rapidly induce effector T cells in the absence of elevated IL-2 and that IL-10 is specifically elevated in certain Th1-like responses.

Animals↗
PubMed1993

Schistosoma japonicum-infected mice show reduced hepatic fibrosis and eosinophilia and selective inhibition of interleukin-5 secretion by CD4+ cells after treatment with anti-interleukin-2 antibodies.

Schistosoma japonicum-infected mice were injected with antibodies to interleukin-2 (IL-2) and/or IL-2 receptor to clarify the role of IL-2 on the granulomatous reaction around schistosome eggs in the liver. Granulomas were of normal or slightly increased size in animals subjected to IL-2 blockade, but hepatic fibrosis was markedly decreased in treated animals 10 weeks after infection. Anti-IL-2 treatment significantly decreased the in vitro secretion of IL-5 by antigen-stimulated spleen cells, and peripheral eosinophilia and tissue eosinophilia were diminished. Secretion of IL-2, IL-4, and gamma interferon was unaffected. Our results indicate that IL-2 is not an essential determinant of granuloma size in S. japonicum-infected mice but that, as in Schistosoma mansoni infection, the development of hepatic fibrosis is critically dependent on IL-2 levels and granuloma size and hepatic fibrosis are differentially regulated.

Animals↗
PubMed1992

Role of antigen-specific T cell help in the generation of in vivo antibody responses. I. Antigen-specific T cell help is required to generate a polyclonal IgG1 response in anti-IgD antibody-injected mice.

A system in which injection of mice with an antibody to mouse IgD that they recognize as foreign stimulates a large, T cell-dependent IgG response was used to study whether Ag-specific T cell help is required to stimulate polyclonal (non-Ag-specific) IgG production in vivo. Igha x Ighb allotype heterozygous mice were injected with a conjugate of a foreign Ag coupled to a mAb specific for one of the two IgD allotypes expressed in these mice. This conjugate cross-links mIgD on B cells that express the recognized allotype. These cells process the conjugate and present the foreign Ag to Ag-specific T lymphocytes, which become activated. Thus, B cells of the recognized allotype can be stimulated by cross-linking of their mIgD, Ag-specific T cell help, non-Ag-specific cytokines, and non-Ag-specific contact with activated T cells. In contrast, B cells that express the Igh allotype not recognized by the Ag-anti-IgD antibody conjugate (bystander B cells) can be stimulated in this system only by non-Ag-specific cytokines and non-Ag-specific contact with activated T cells. Although both recognized and bystander B cells in conjugate-injected mice demonstrated substantial increases in size and Ia expression, only the recognized B cells were induced to synthesize DNA and to make a substantial polyclonal Ig response. Bystander B cells still failed to secrete IgG when mice were injected with an anti-IgD-Ag conjugate specific for the other Igh allotype as well as a mAb that cross-linked IgD of the bystander B cell allotype. These observations demonstrate that although non-Ag-specific cytokine and contact-mediated T cell help are sufficient to induce B cells to increase in size and Ia expression in anti-IgD antibody-injected mice, Ag-specific T cell help is required to stimulate the generation of an IgG response in these mice.

Animals↗
PubMed1992

Role of antigen-specific T cell help in the generation of in vivo antibody responses. II. Sustained antigen-specific T cell help is required to induce a specific antibody response.

The injection of mice with a goat or rabbit antibody to mouse IgD stimulates a large polyclonal IgG response, approximately 10% of which is specific for antigenic determinants on the anti-IgD antibody molecule. The large goat IgG (GIgG)-specific antibody response in mice injected with goat antibody to mouse IgD requires that GIgG-specific B cells undergo much greater clonal expansion than B cells specific for other Ag. One possible explanation for the greater clonal expansion of GIgG-specific B cells is that B cells that lack GIgG specificity can only be stimulated with GIgG-specific T help during the relatively short time that anti-IgD binds to, and is processed and presented by, these B cells before they cease to express membrane mIgD. In contrast, GIgG-specific B cells can continue to bind, process, and present GIgG through mIgM after they lose mIgD. To test the hypothesis that extended stimulation with Ag-specific T help is required to generate a specific antibody response, we determined time requirements for Ag-specific T cell help for the development of such a response. Mice were injected with rabbit antibody to mouse IgD plus one or more daily injections of FITC conjugated to a F(ab')2 fragment of rabbit IgG (FITC-(Fab')2), which has a short in vivo half-life, and IgG1 anti-FITC antibody production was analyzed. In this system, each additional injection of FITC-F(ab')2 extends the period during which FITC-specific B cells can process this Ag and present it to rabbit IgG-specific T cells. Each additional injection of FITC-F(ab')2 stimulated a several-fold increase in IgG1 anti-FITC antibody levels, and injections on 5 consecutive days were required to induce a maximal anti-FITC response. These observations provide evidence that sustained Ag-specific T cell help is required to stimulate the degree of B cell clonal expansion that characterizes a specific antibody response.

Animals↗
PubMed1992

Ig mu-epsilon isotype switch in IL-4-treated human B lymphoblastoid cells. Evidence for a sequential switch.

IgE is produced by B lymphocytes that have undergone a deletional rearrangement of their Ig H chain gene locus, a rearrangement that joins the switch region of the mu gene, S mu, with the corresponding region of the epsilon gene, S epsilon. To examine the resulting composite S mu-S epsilon junctions of human lymphoid cells, we have used a polymerase chain reaction strategy to clone the switch regions of the human myeloma U266 and of two IgE-producing human cell lines generated by treatment of lymphocytes with EBV plus IL-4. The switch junction of one of the EBV lines is a complex rearrangement in which a fragment of S gamma is interposed between S mu and S epsilon. This finding suggested that the switch to epsilon in this human lymphoid cell was preceded by a S mu-S gamma recombination. To determine whether this sequential switch rearrangement represented a unique event or occurred with some regularity in human B cells switching to IgE production, DNA samples from bulk cultures of lymphocytes treated with IL-4 were subjected to polymerase chain reaction amplification of their S mu-S epsilon junctions. When the resulting fragments were examined by Southern blotting, a substantial fraction hybridized to an S gamma probe. This finding suggests that sequential recombination involving S gamma is not rare in the switch to epsilon production in humans. Our polymerase chain reaction strategy should be useful in studying isotype switching at the DNA level.

B-Lymphocytes↗
PubMed1992

Treatment with anti-IL-2 antibodies reduces hepatic pathology and eosinophilia in Schistosoma mansoni-infected mice while selectively inhibiting T cell IL-5 production.

Granulomas around Schistosoma mansoni eggs are a principal cause of morbidity in mice infected with this helminth. In vivo treatment of infected mice with anti-IL-2 antibodies, with or without anti-IL-2 receptor antibodies, significantly diminished the size of circumoval granulomas in the liver and decreased hepatic fibrosis to half that in untreated mice. Antibody-treated animals also displayed a marked reduction in both peripheral blood and tissue eosinophilia while IgE levels were unchanged or increased. Spleen cell cytokine production in response to Ag or mitogen stimulation was selectively altered by in vivo anti-IL-2 administration. IL-5 responses were dramatically reduced, whereas IL-4, IL-2, and IFN-gamma responses were not consistently changed. These findings confirm previous observations, suggesting a role for IL-2 in egg-induced pathology but indicate that the primary function of this cytokine in schistosome-infected mice may be in the generation of Th2- rather than Th1-associated responses.

Animals↗
PubMed1992

Induction of IgG3 secretion by interferon gamma: a model for T cell-independent class switching in response to T cell-independent type 2 antigens.

T cell-independent type 2 (TI-2), in contrast to T-dependent, antigens stimulate the production of murine IgG3. To investigate a possible role for cytokines in mediating the induction of this IgG subclass, we established an in vitro polyclonal model system for studying TI-2 antigen-mediated B cell activation by using dextran-conjugated anti-IgD antibody (alpha delta-dex). We demonstrate that interferon gamma (IFN-gamma) stimulates, and interleukin 4 inhibits, the expression of IgG3 by alpha delta-dexactivated cells. The production of IFN-gamma by non-T cells in response to bacterial products, possibly capsular polysaccharides, may provide an explanation underlying the ability of TI antigens, which are unable to directly stimulate T cell-derived cytokines to induce Ig isotype switching.

Animals↗
PubMed1992

Co-crosslinking Fc epsilon RII/CD23 and B cell surface immunoglobulin modulates B cell activation.

Previous studies have shown that a highly multivalent from of anti-IgD or anti-IgM, prepared by conjugating the respective antibodies to dextran, causes extensive B cell proliferation with ng/ml concentrations of the anti-immunoglobulin (Ig). A modification of this system has been exploited to investigate the effect of co-crosslinking the Fc epsilon RII and surface Ig by binding DNP to the dextran backbone (DNP-dextran) and employing a DNP-specific monoclonal IgE of either rat or mouse origin. Addition of anti-IgD-(H delta a/1)[DNP-dextran] or anti-IgM-[DNP-dextran] to purified, resting murine B cells resulted in B cell proliferation over a broad dose (0.03-30 micrograms/ml). Addition of DNP-specific rat or mouse IgE dramatically modulated the proliferative response. Proliferation in response to doses greater than 0.3 microgram/ml H delta a/1-[DNP-dextran] was consistently reduced in a dose-dependent manner in the presence of increasing amounts of IgE while proliferation to lower concentrations of H delta a/1-[DNP-dextran] was slightly enhanced or not influenced at all by the IgE anti-DNP. Interleukin-4 (IL-4) significantly increased the IgE effect, in line with its known enhancing effects on Fc epsilon RII levels. Experiments measuring Ig production rather than proliferation demonstrated that in the presence of IgE anti-DNP, B cells produced lower amounts of immunoglobulin (IgG1 or IgM) in response to an anti-Ig signal. Control experiments demonstrated that the IgE effect on proliferation was blocked by monoclonal anti-Fc epsilon RII, but not anti-Fc gamma RII, thus demonstrating the necessity for IgE/Fc epsilon RII interaction. In addition, the necessity for co-crosslinking was shown by the inability of IgE anti-DNP to affect the proliferative response to H delta a/1-dextran even in the presence of various doses of DNP-dextran. These results demonstrate that co-crosslinking of sIg and the Fc epsilon RII results in an altered B cell response to anti-Ig mediated activation. IL-4 does not ablate this inhibition, in contrast to the effect of co-crosslinking Fc gamma RII and surface Ig, suggesting a model whereby IgE can modulate its own production.

Animals↗
PubMed1992

Effect of interferon-gamma on myelin basic protein-specific T cell line proliferation in response to antigen-pulsed accessory cells.

We have shown previously that treatment of SJL/J mice with anti-interferon-gamma monoclonal antibody (mAb) exacerbated experimental allergic encephalomyelitis (EAE) only if administered at the time of encephalitogenic challenge. Here we investigate the role of interferon-gamma (IFN-gamma) and anti-IFN-gamma mAb in the early events of T cell activation in vitro. Pretreatment of murine peritoneal exudate cells (PEC) with IFN-gamma led to a significant increase in their ability to activate myelin basic protein (MBP)-specific, short-term T cell lines. When exogenous IFN-gamma was added to cocultures of T cells and MBP-pulsed PEC, the antigen-specific T cell proliferation was considerably reduced. Anti-IFN-gamma mAb added to these cultures neutralized the inhibitory effect of the exogenous IFN-gamma on T cell proliferation but had no visible effect on class II MHC expression by the antigen-pulsed PEC present in the same cultures. A reduction in T cell proliferation was also observed when the T cells were treated with IFN-gamma prior to coculture with the MBP-pulsed PEC. These results demonstrate that, on one hand, IFN-gamma enhances the ability of PEC to induce antigen-specific T cell proliferation but, on the other hand, acts on the T cells themselves by inhibiting their proliferation in response to the antigen-pulsed PEC. This may explain why treatment with anti-IFN-gamma antibody in vivo induces EAE exacerbation.

Animals↗
PubMed1992

Effect of anti-interferon-gamma and anti-interleukin-2 monoclonal antibody treatment on the development of actively and passively induced experimental allergic encephalomyelitis in the SJL/J mouse.

SJL/J mice challenged with myelin basic protein (MBP) in complete Freund's adjuvant (CFA) developed only mild chronic-relapsing experimental allergic encephalomyelitis (EAE) with very low incidence. However, treatment of challenged mice with anti-interferon-gamma (IFN-gamma) monoclonal antibody (mAb) determined severe disease in all cases. Similarly, in passive EAE, the addition of anti-IFN-gamma to the in vitro MBP-activated cells at the time of transfer led to significant disease exacerbation in all recipients. The disease enhancing effect was observed only when the mAb was given at the time of active challenge or of passive transfer, but not at later times. Anti-interleukin-2 (IL-2) antibody had only a marginal effect in the active induction, but drastically reduced the manifestations of passive EAE, even when mixed with a disease-enhancing dose of anti-IFN-gamma. These findings support the notion that IL-2 is required for disease induction whereas IFN-gamma plays a disease-limiting role early in the development of EAE.

Animals↗
PubMed1992

Cytokines: making the right choice.

Fred Finkelmon and Joseph Urban propose that optimal host defense against different classes of parasite depends upon induction of different sets of immune effector mechanisms, which are, in turn, dependent upon secretion of different sets of cytokines. The authors suggest that hosts identify characteristics common to parasites of a given type as those triggers that stimulate secretion of the proper cytokine set.

Journal Article↗
PubMed1992

Antigen presentation by B lymphocytes to CD4+ T lymphocytes in vivo: importance for B lymphocyte and T lymphocyte activation.

B lymphocytes, like macrophages and dendritic cells, can present antigen to CD4+ T cells. Antigen presentation by B cells is essential for the generation of an in vivo T cell dependent antibody response, and repeated antigen presentation by B cells to T cells is necessary to induce B cell clonal expansion. Presentation of antigen by resting B cells to unprimed T cells tolerizes T cells, while anti-IgD antibody activates B cells and allows B cell antigen presentation that productively activates T cells. However, activation is not all that is required for B cells to productively present antigen to T cells.

Animals↗
PubMed1991

Regulation by interferon alpha of immunoglobulin isotype selection and lymphokine production in mice.

Antigens and infectious agents that stimulate interferon alpha(IFN-alpha) production in mice induce antibody responses that are predominantly of the immunoglobulin (Ig)G2a isotype and contain little or no IgE. This suggested the possibility that IFN-alpha might have a role in directing Ig isotype selection. Consistent with this possibility, we have found that injection of mice with recombinant mouse IFN-alpha suppresses IgE secretion, enhances IgG2a secretion, and has no independent effect on IgG1 secretion in mice stimulated with a foreign anti-IgD antibody. Injection of mice with polyinosinic acid.polycytidylic acid (poly I.C), an inducer of macrophage IFN-alpha production, also suppresses the anti-IgD antibody-induced IgE response and stimulates the IgG2a response; these effects are blocked by a sheep antibody that neutralizes mouse IFN-alpha/beta. Both recombinant IFN-alpha and poly I.C have maximum IgE suppressive and IgG2a stimulatory effects when injected early in the anti-IgD antibody-induced immune response. Addition of IFN-alpha to mouse B cells cultured with lipopolysaccharide (LPS) + interleukin 4 (IL-4) suppresses both IgG1 and IgE production, but much less potently than IFN-gamma. IFN-alpha suppresses anti-IgD antibody-induced increases in the level of splenic IL-4 mRNA, but enhances the anti-IgD antibody-induced increase in the splenic level of IFN-gamma mRNA. These results are consistent with the effect of IFN-alpha on Ig isotype expression in mice, as IL-4 stimulates IgE and suppresses IgG2a secretion while IFN-gamma exerts opposite effects. These observations suggest that antigen presenting cells, by secreting IFN-alpha early in the course of an immune response, can influence the nature of that response both through direct effects on B cells and by influencing the differentiation of T cells.

Animals↗
PubMed1991

IgD receptors on murine T-helper cells bind to Fd and Fc regions of immunoglobulin D.

Receptors for immunoglobulins on animal cells invariably show specificity for Fc regions of the protein and are hence called Fc receptors. The present study shows that immunoglobulin D receptors present an exception to this rule. Binding of IgD-coated erythrocytes to murine IgD-receptor-bearing T-helper cells is competitively inhibited by IgD, by its Fab delta fragments, and by deletion mutants of IgD lacking (i) the first constant domain of the delta heavy chain (KWD1), (ii) that region plus the delta heavy-chain-hinge region (KWD6), or (iii) the third constant domain of the delta heavy chain (Gen. 24). KWD1, Gen. 24, or KWD6 mutants bind to T-helper cells bearing receptors for IgD independently of each other. Furthermore, Gen. 24 and KWD6 mutants also competitively inhibit binding of each other in cross-blocking experiments. These results show that the IgD receptors binds to the Fd delta and the Fc delta and cannot readily be explained by sequence homology between the two parts of the IgD molecule.

Amino Acid Sequence↗