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PubMed1987

Quantitation of T-macrophage binding avidity with and without antigen using a novel centrifugation assay.

The T cell-macrophage interaction, necessary for T cell activation, has nonspecific and specific components. Nonspecific T-macrophage interactions are mediated by surface glycoproteins such as LFA 1, 2 and 3, while specific interactions are mediated by the T3-Ti complex on the T cell and antigen plus Ia molecules on the macrophage. To determine the relative contributions of specific antigen to the total avidity of T-macrophage binding we adapted a novel assay capable of providing quantitative estimations of the avidity of cell-cell interactions. Using this assay we determined the avidity of a cloned CD4+ antigen specific T cell line for autologous macrophages with and without antigen. The presence of specific antigen increased binding avidity by approximately 25%. This assay should prove useful in further characterizing the avidity of T-macrophage interactions.

Antigens↗
PubMed2002

Can the low-avidity self-specific T cell repertoire be exploited for tumor rejection?

Can self-specific T cells that have escaped intrathymic deletion be exploited to generate antitumor immunity? To determine whether antitumor immunity to a self-Ag for which central tolerance exists can be generated, a mouse model is used in which a fragment of the influenza nucleoprotein (NP) is expressed as a transgene under the control of the H-2K promoter in C57BL/10 mice (B10NP mice). In these mice an oligoclonal population of NP-specific T cells escapes thymic and peripheral deletion and can be activated upon immunization. The main hallmark of these self-specific CD8(+) T cells is diminished avidity for the pertinent MHC/peptide complex. We show in this study that intranasal infection with influenza virus can stimulate low-avidity NP-specific T cells to recognize and destroy NP-expressing microtumors in the lung, but not NP-expressing tumors growing s.c. Only a memory NP-specific CD8(+) T cell response can suppress the growth of an s.c. growing NP-expressing tumor. This delay in tumor growth is associated with a dramatic increase in the number of circulating NP-specific CD8(+) T cells. In addition, cultured memory NP-specific T cells require approximately 100-fold less Ag to induce NP-specific lysis than primary T cells, consistent with the observation that memory T cells have an increased avidity due to affinity maturation. Finally, during an NP-specific memory response, substantial numbers of low-avidity NP-specific T cells can be recovered from s.c. growing tumors. Together, these findings indicate that, when only a low-avidity repertoire is available to generate antitumor immunity, the best strategy may be to enhance memory responses.

Animals↗
PubMed2002

Antimelanoma activity of CTL generated from peripheral blood mononuclear cells after stimulation with autologous dendritic cells pulsed with melanoma gp100 peptide G209-2M is correlated to TCR avidity.

Anchor residue-modified peptides derived from tumor-associated Ag have demonstrated success in engendering immune responses in clinical studies. However, tumor regression does not always correlate with immune responses. One hypothesis to explain this is that CTL resulting from such immunization approaches are variable in antitumor potency. In the present study, we evaluated this hypothesis by characterizing the activity of tumor-associated Ag-specific CTL. We chose an anchor residue-modified peptide from gp100, G209-2M, and used peptide-pulsed dendritic cells to generate CTL from PBMC of HLA-A2(+) normal donors. The specificities and avidities of the resulting CTL were evaluated. The results demonstrate that CTL generated by G209-2M can be classified into three categories: G209-2M-specific CTL which are cytotoxic only to G209-2M-pulsed targets; peptide-specific CTL which recognize both G209 and G209-2M peptides but not melanomas; and melanoma-reactive CTL which recognize peptide-pulsed targets as well as HLA-A2(+)gp100(+) melanomas. CTL that kill only peptide-pulsed targets require a higher peptide concentration to mediate target lysis, whereas CTL that lyse melanomas need a lower peptide concentration. Increasing peptide density on melanomas by loading exogenous G209 peptide enhances their sensitivity to peptide-specific CTL. High avidity CTL clones also demonstrate potent antimelanoma activity in melanoma model in nude mice. Injection of G209 peptide around transplanted tumors significantly enhances the antitumor activity of low avidity CTL. These results suggest that peptide stimulation causes expansion of T cell populations with a range of avidities. Successful immunotherapy may require selective expansion of the higher-avidity CTL and intratumor injection of the peptide may enhance the effect of peptide vaccines.

Animals↗
PubMed2003

Homology between an alloantigen and a self MHC allele calibrates the avidity of the alloreactive T cell repertoire independent of TCR affinity.

The self-restricted T cell repertoire exhibits a high frequency of alloreactivity. Because these alloreactive T cells are derived from the pool of cells selected on several different self MHC alleles, it is unknown how development of the alloantigenic repertoire is influenced by homology between a self MHC allele and an alloantigen. To address this, we used the 2C transgenic TCR that is selected by K(b), is alloreactive for L(d), and cross-reacts with L(q). L(q) is highly homologous to L(d) and binds several of the same peptide ligands, including p2Ca, the peptide recognized by 2C. We find that L(d)/p2Ca is a high avidity agonist ligand, whereas L(q)/p2Ca is a low avidity agonist ligand for 2C T cells. When mice transgenic for the 2C TCR are bred to L(q)-expressing mice, 2C(+) T cells develop; however, they express lower levels of either the 2C TCR or CD8 and require a higher L(d)/p2Ca ligand density to be activated than 2C(+) T cells selected by K(b). Furthermore, the 2C T cells selected in the presence of L(q) fail to detect L(q)/p2Ca complexes even at high ligand density. Thus, despite possessing the identical TCR, there is a functional avidity difference between 2C(+) T cells selected in the presence of L(q) vs K(b). These data provide evidence that homology between the selecting ligand and an alloantigen can influence the avidity of the T cell repertoire for the alloantigen, and suggest that thymic selection can fine tune T cell avidity independent of intrinsic TCR affinity.

Alleles↗
PubMed2005

Multiple costimulatory modalities enhance CTL avidity.

Recent studies in both animal models and clinical trials have demonstrated that the avidity of T cells is a major determinant of antitumor and antiviral immunity. In this study, we evaluated several different vaccine strategies for their ability to enhance both the quantity and avidity of CTL responses. CD8(+) T cell quantity was measured by tetramer binding precursor frequency, and avidity was measured by both tetramer dissociation and quantitative cytolytic function. We have evaluated a peptide, a viral vector expressing the Ag transgene alone, with one costimulatory molecule (B7-1), and with three costimulatory molecules (B7-1, ICAM-1, and LFA-3), with anti-CTLA-4 mAb, with GM-CSF, and combinations of the above. We have evaluated these strategies in both a foreign Ag model using beta-galactosidase as immunogen, and in a "self" Ag model, using carcinoembryonic Ag as immunogen in carcinoembryonic Ag transgenic mice. The combined use of several of these strategies was shown to enhance not only the quantity, but, to a greater magnitude, the avidity of T cells generated; a combination strategy is also shown to enhance antitumor effects. The results reported in this study thus demonstrate multiple strategies that can be used in both antitumor and antiviral vaccine settings to generate higher avidity host T cell responses.

Adjuvants, Immunologic↗
PubMed2000

[Determination of specific immunoglobin G avidity in serodiagnosis of toxoplasmosis].

A total of 37 serum samples from pregnant women were examined for the avidity of toxoplasma IgG antibodies using commercially available enzyme immunoassay (Vidas Toxo IgG Avidity, bio Merieux). Low values of the avidity index were found for 4 samples and borderline ones were found in further 3 cases. Out of 19 serum samples showing the presence of IgG and IgM toxoplasma antibodies, 13 had high avidity index, including 9 samples from women in the first trimester of pregnancy. The results of examinations in these 9 cases allowed to exclude the possibility that toxoplasma infection was acquired during gestation. It is to be concluded that determinations of antitoxoplasma IgG avidity should become routine in every pregnant woman positive in the test for specific IgM antibody.

Animals↗
PubMed2001

Increased TCR avidity after T cell activation: a mechanism for sensing low-density antigen.

While activated T cells are known to have enhanced biological responses to antigen stimulation, the biophysical basis of this increased sensitivity remains unknown. Here, we show that, on activated T cells, the TCR avidity for peptide-MHC complexes is 20- to 50-fold higher than the TCR avidity of naive T cells. This increased avidity for peptide-MHC depends on TCR reorganization and is sensitive to the cholesterol content of the T cell membrane. Analysis of the binding data indicates the enhanced avidity is due to increases in cross-linking of TCR on activated T cells. Activation-induced membrane (AIM) changes in TCR avidity represent a previously unrecognized means of increasing the sensitivity of activated T cells to small amounts of antigen in the periphery.

Animals↗
PubMed2000

[Titer and avidity of serum antibody to Porphyromonas gingivalis before and after periodontal therapy].

OBJECTIVE: To observe the changes of titer and avidity of serum antibody to Porphyromonas gingivalis (Pg) before and one month after periodontal therapy, and to observe the correlation of titer and avidity of anti-Pg IgG with clinical indices. METHODS: ELISA and DEA-ELISA were used to determine the titer and avidity of serum IgG antibody to Pg381 before and one month after periodontal treatment in 17 periodontitis patients and 6 healthy control subjects. RESULTS: The titers of anti-Pg IgG antibody were higher in periodontitis patients than in healthy control subjects (P < 0.001). All patients were seropositive (titers to Pg were higher than 2-fold above the median for control subjects). IgG antibody avidity to Pg in periodontitis patients were not found to be significantly lower than that in control group. The titers to Pg decreased significantly at one month after periodontal therapy, but antibody avidity didn't change. Serum anti-Pg antibody titers had a tendency of negative correlation with probing depth. The antibody titers were significant higher in periodontitis patients with < or = 5 mm mean probing depth than in patients with > 5 mm mean probing depth. CONCLUSIONS: It is suggested that the humoral immune response to Pg381 is protective and this protective effect mainly depends on the titer of antibody.

Antibodies, Bacterial↗
PubMedDate not supplied

Specific IgG avidity in acute and chronic human fascioliasis.

The detection of IgG avidity in sera is potentially useful in the diagnosis of acute and chronic infection. We studied IgG avidity in 31 patients with fascioliasis, with the aim of evaluating the clinical application of this test to confirm the diagnosis of incubating cases and to distinguish between acute and chronic cases. Of the 31 cases, 13 were incubating and had a mean avidity index of 57.28 +/- 5.79%. The 18 chronic cases had an avidity index of 68.80 +/- 8.92%. The difference was highly significant. We conclude that IgG avidity is a reliable means of identifying the stage of fascioliasis and suggest a cut-off point of 59.90% to distinguish between acute and chronic infection.

Adolescent↗
PubMed2004

[Immunoglobulin G avidity in infectious diseases].

The paper reviews results reached so far about avidity of immunoglobulins G in viral, parasitic and bacterial infectious diseases. The general introductory part begins with explanation of immunologic basis in maturation of avidity of immunoglobulins G and proceeds up to a survey of methods used for the determination of avidity. It also deals with the modes of evaluation in these methods and comments on their advantages and disadvantages. The part devoted to individual infectious diseases brings the most important information about avidity of immunoglobulins G in specific infections, especially in view of their (even potential) practical medical application, mainly in determining the phase of infection in pregnant women and in patients after transplantation. The highest attention is paid to herpes virus infections, especially the cytomegalous virus and the infections with Epstein-Barr virus, rubella and toxoplasmosis, therefore those infections, which in the given situations clearly demonstrated the contribution of avidity analysis in the solution of interpretation-difficult conditions typical for serology, such as lasting levels of immunoglobulins M and cross-reactivity of antibodies.

Antibody Affinity↗
PubMed2004

Avidity as a parameter for diphtheria vaccine efficacy.

The avidity of antibodies (Abs) to diphtheria Toxin (DT), toxoids (DTo) and the DT binding site (DTBS) was investigated in sera from guinea bigs vaccinated with various DTo. Measurement of avidity by the thiocyanate procedure revealed that, the maturation patterns of Abs to the corresponding DTo were not much different whereas the maturation patterns of Abs to DT were different. Differences up to 20 folds were observed in the affinity to the DTBS as measured by the tissue culture procedure and expressed as equilibrium constant (K). The avidity of Abs to either the corresponding DTo or the DT could not be correlated to the vaccine efficacy, whereas the vaccine efficacy could be ranked according to its affinity to the DTBS. This may be explained in terms of the specificity of measurement in each procedure. The thiocyanate procedure measures the average avidity to complex antigens with several epitopes whereas the tissue culture procedure allows determination of the affinity of Abs to the DTBS. It is concluded that in assessment of new vaccines, attention should be given to including measurement of the avidity of Abs to known protective epitopes rather than to complex antigens or a mixture of antigens.

Animals↗
PubMed1979

Passive immune complex glomerulonephritis in mice: models for various lesions found in human disease. II. Low avidity complexes and diffuse proliferative glomerulonephritis with subepithelial deposits.

Intravenous injections of mice three times a day for 3 days with soluble complexes of 3 mg. of moderately avid rabbit antibody to chicken egg albumin prepared by dissolution of equivalence precipitates in 80 times the equivalence amount of antigen resulted in a combined mesangial and loop localization of immune complexes. With complexes formed from antibody of low avidity, injected four times a day for 3 days, a predominately subepithelial loop deposition of complexes was observed. Complexes formed from moderately avid antibody gave rise to a mainly mesangiopathic glomerulonephritis, whereas low avidity complexes were associated with a diffuse glomerulonephritis. These results, in combination with those of the previous paper, successfully reproduce the basic form of the lesions seen in active immune complex disease by passive means and suggest that antibody avidity is a major determinant of the site of localization of immune complexes and therefore of the morphologic form of the resulting glomerulonephritis. The importance of these observations for our understanding of the pathogenesis of human immune complex disease is considered.

Animals↗
PubMedDate not supplied

[Enzyme immunoassay system for the detection of low-avid lgG antibodies to human cytomegalovirus ("CMV-diagnost")].

The new Russian enzyme immunoassay system "CMV-Diagnost" based on the detection of low-avid IgG antibodies has been developed for the rapid diagnosis of cytomegalovirus infection. The system was found not only to determine the strained immunity in response to cytomegalovirus, but also to judge the current infection from the avidity index of detectable IgG antibodies with a high degree of validity. The antibody avidity index of less than 30% suggests an acute stage of primary cytomegalovirus infection. The minimum antibody threshold bodies (deltaOD has been established for the correct interpretation of data on low-avid antibodies. deltaOD of > or =0.6 optic units was for the developed test system "CMV-Diagnost. A correlation was found between the serum levels of low-avid antibodies and IgM antibodies to cytomegalovirus at the acute stage of the disease.

Adolescent↗
PubMed2004

[Use of specific immunoglobulin G antibody avidity in the differential diagnosis of active and chronic Toxocara canis infections].

To differentiate between acute and past Toxocara canis infections, a modified enzyme-linked immunosorbent assay, based on the dissociation of antigen-antibody complex with 6 M urea solution was used to measure levels of avidity of specific immunoglobulin G antibody against Toxocara canis excretory-secretory antigen. IgG avidity index was determined in the sera of 212 patients, divided into two groups with various stages of Toxocara infection. Patients were classified according to time period, from the onset of clinical symptoms or first positive serology result. Low IgG avidity index was found in the sera of 6.6% of patients in the acute phase, and all samples from the chronic stage of infection were characterized by high avidity values above 0.5 (mean 0.74). It was documented, that the avidity test for specific IgG antibodies is a valuable diagnostic method that helps to distinguish the early from the later phase of Toxocara canis infection. Indications for anti-parasitic treatment according to immunological activity of Toxocara infection were discussed.

Adolescent↗
PubMed1985

Influence of avidity of circulating anti-DNA antibodies on murine lupus nephritis.

We determined the avidity of antiDNA antibodies in plasma of NZB/W mice when nephritis became apparent, when such mice developed chronic glomerulonephritis, and in mice whose nephritis was arrested, or attenuated, by immunosuppression. Antibody avidity was estimated by the rate of dissociation of 125IDNA-antiDNA complexes when excess unlabelled DNA was added to the plasma. In all groups of mice studied, the relative contributions of high and low avidity antiDNA antibodies were comparable and, overall, high avidity antibodies predominated. The results indicate that the avidity of circulating antiDNA antibodies did not reflect the extent and type of glomerular involvement, and was not predictive of clinical course.

Animals↗
PubMed1976

[Avidity criteria in assessing the functional activity of antigens, antibodies and non-specific serum inhibitors on a model of the kinetic reaction of hemagglutination suppression with arboviruses].

The functional activity of some arboviruses of groups A and B, of the antibodies and serum inhibitors was studied on a model of the kinetic hemagglutination inhibition test (HAI) by different avidity criteria (velocity, completeness and stability of formation of a neutral complex). The avidity indices of the antigens, antibodies and the inhibitors proved to depend on the group, species and strain peculiarities of the arboviruses, the method of preparation of the antigen, the biological species of the donor of the immune and normal blood sera, the method of treatment of the sera and a number of other factors. There proved to be no constan-correlation between the avidity of the strain and the avidity of the serum immune to it. Inhibitors of the normal rabbit and human sera were not less effective in comparison with the specific antibodies to a number of viral strains of tick-borne encephalitis and Japanese encephaliti or even exceeded them by the avidity indices to the antigens in the HAI test. The most active (functionally) strains can be recommended for obtaining high-quality viral (antigenic and serum) preparations.

Animals↗
PubMed1978

[Assessment of the degree of antibody avidity in food toxinfections of salmonellal etiology using the indirect hemagglutination inhibition reaction].

The authors studied the avidity of antibodies in the sera obtained from 56 patients suffering from salmonelloses, the causative agents of which were referred to groups B, C1, C2, E. Determinations were carried out in the indirect hemagglutination inhibition test. It was shown that the mentioned test could be used to assess the extent of the serum antibodies avidity. Age-specific avidities of the serum antibodies were revealed in patients suffering from salmonella infections during the infectious process. There was found an insignificant prevalance of the antibody avidity in the patients with the forms of the disease of moderate severity and severe. In the patients with salmonelloses of group B the antibodies proved to be the most avid.

Antibodies, Bacterial↗
PubMed1995

Autoimmunity caused by ignorant CD8+ T cells is transient and depends on avidity.

RIP-Kb mice, which express H-2Kb (Kb) molecules on their pancreatic beta cells, were used to examine the requirements for induction of autoimmune diabetes caused by CD8+ T cells. Previous studies showed that when these mice were crossed to mice expressing a Kb-specific TCR transgene, those CD8+ cells expressing the highest density of the transgenic TCR (presumably the highest avidity cells) were deleted intrathymically due to aberrant expression of Kb at this site. The remaining low avidity cells ignored Kb-bearing beta cells, even after priming, but were able to cause autoimmune diabetes when supplied with Il-2. To examine the properties of high avidity autoreactive CD8+ T cells, the thymic compartment of RIP-Kb mice was replaced with normal tissue to enable the maturation of CD8+ cells expressing the highest density of the transgenic TCR. These high avidity cells generally ignored Kb-expressing beta cells, but became autoaggressive after priming. Importantly, analysis of islet infiltration by CD8+ T cells revealed the presence of infiltrating cells in all mice examined within 3 wk of priming, but such infiltration was not usually apparent at later time points. In some cases, multiple primings were necessary for full development of autoimmunity. This implied that beta cells could act as transient targets for CD8+ T cell attack but could not sustain the stimulation of primed CD8+ cells. These studies indicate that the duration of priming stimulus and the avidity of the autoreactive CD8+ cells profoundly influence the severity of autoimmune disease.

Animals↗