The anti-idiotypic antibody 1F7 selectively inhibits cytotoxic T cells activated in HIV-1 infection.
(65/2060)
Circulating CD8+ T lymphocyte numbers rise substantially following infection with HIV-1. This expanded CD8+ T cell population includes HIV-specific CTL and CTL that kill activated uninfected CD4+ lymphocytes. Experimental, epidemiological and clinical evidence supports the possibility that expansion of CD8+ CTL contributes to CD4+ T cell depletion and disease progression in human HIV infection. Therefore, modulation of CD8+ T cell numbers or of certain CD8+ CTL activated in HIV-infected individuals may be beneficial. It was found that 1F7, a mAb against an idiotype common to anti-HIV and anti-simian immunodeficiency virus (SIV) antibodies, selectively inhibited both anti-HIV CTL and CTL against uninfected CD4+ T cells. Alloantigen-specific CTL and NK cells from either HIV-infected individuals or controls were unaffected by 1F7. Prolonged incubation of CD8+ T cells from HIV-infected individuals with 1F7 induces apoptosis, which was shown to be reflected functionally in reduced total CTL activity and in especially reduced CTL activity against uninfected CD4+ lymphocytes. The selective reactivity of 1F7 with certain CD8+ CTL could be applied towards the modulation of CD8+ T cell responses involved in AIDS pathogenesis. (+info)
A neoadjuvant clinical trial in colorectal cancer patients of the human anti-idiotypic antibody 105AD7, which mimics CD55.
(66/2060)
Thirty-five patients received 105AD7 human anti-idiotype vaccination prior to surgery for colorectal carcinoma. Patients were immunized before and also received one to two immunizations after surgical resection of their colorectal cancer. The vaccine was well tolerated with no associated toxicity. Lymphocytic infiltration within the resected tumors was quantified by immunohistochemistry and image analysis. Enhanced infiltration of helper T cells (CD4) and natural killer (NK) cells (CD56) were observed in the tumors from immunized patients when compared with tumors from stage, grade, site, age, and sex matched unimmunized patients. NK activity was increased in the blood, peaking 7-10 days post immunization and then dropping rapidly and correlating with NK extravasation within the tumor. Comparison of the amino acid sequences of 105AD7 anti-idiotype and the antigen it mimics, CD55, has predicted that patients with HLA-DR1, HLA-DR3, and HLA-DR7 haplotypes should show helper T cell responses following 105AD7 vaccination. Eighty-three percent of patients expressing these haplotypes responded to 105AD7, whereas 88% of patients who failed to express these haplotypes were nonresponders. With a median follow-up of 4 years (range, 2.5-6 years) 65% of patients remained disease free. This trial shows that 105AD7 stimulates antitumor inflammatory responses allowing extravasation within tumor deposits of both helper T cells and NK cells. This represents a way of evaluating immune responses in patients both within the blood and at the tumor site. The study confirms that immunization with a human anti-idiotypic antibody results in immune responses in 83% of patients with a permissive haplotype. (+info)
Cross-reactivity of antiidiotypic antibodies with DNA in systemic lupus erythematosus.
(67/2060)
OBJECTIVE: To assess the functional relationship between antibodies reactive with DNA and antibodies reactive with the idiotypes (idiopeptides) of anti-DNA antibodies that are associated with systemic lupus erythematosus (SLE) in mice. METHODS: Antiidiotypic antibodies that appeared spontaneously in lupus mice, and others that were induced by immunization of normal, non-lupus mice, were analyzed for their reactivity by a range of direct binding, competition enzyme-linked immunosorbent assay (ELISA), and surface plasmon resonance (SPR) methods. Their reactions were assessed against synthetic peptides representing sequences of the V(H) region of anti-DNA monoclonal antibody (mAb) V-88, against the native mAb itself, and against mammalian DNA. RESULTS: In lupus mice, only sera with the highest reactivity against double-stranded DNA (dsDNA) also reacted with idiopeptides in ELISA, and this showed a strong statistical correlation. However, there was no significant relationship between antiidiotypic antibodies and anti-single-stranded DNA antibodies. Immunization of (BALB/c x NZW)F1 mice with idiopeptides p64 (V(H) residues 64-80) or p92 (V(H) residues 92-105) induced antibodies that reacted not only against the respective peptides, but also against the native parent anti-DNA mAb V-88. Furthermore, the immune antiidiopeptide antibodies cross-reacted with dsDNA. Competition SPR experiments with the BIAcore system supported this observation. The binding reaction of V(H) peptide p64 (representing the CDR-H2/FR-H3 region of V-88) with antiidiopeptide antibodies was inhibited by dsDNA. CONCLUSION: This study identified a unique set of autoantibodies in SLE. They react with both autoantibody idiotopes and with dsDNA, thus having a dual specificity for 2 autoantigens. Because these antiidiotope antibodies arise naturally during the development of lupus disease, and because they bind also to dsDNA, this provides a mechanism whereby the production of anti-dsDNA antibodies is stimulated. These idiotopes on autoantibodies in lupus act as natural mimotopes for inducing anti-dsDNA antibodies, which, due to their dual specificity, may significantly contribute to the pathology of nephritis in SLE. (+info)
B cell development and activation defects resulting in xid-like immunodeficiency in BLNK/SLP-65-deficient mice.
(68/2060)
Engagement of the B cell receptor (BCR) leads to the activation of tyrosine kinases and other signaling molecules that ultimately determine the type and magnitude of the B lymphocyte's cellular response. The adaptor protein BLNK/SLP-65 plays a pivotal role in BCR signal transduction by coupling Syk activation to downstream elements such as Grb2, phospholipase C-gamma, Vav and Nck. We have generated BLNK(-/-) mice to determine the physiological role of this protein in B cell development and activation. BLNK(-/-) mice exhibit an incomplete block in B cell development with a severe inhibition of pro-B to pre-B cell differentiation. BLNK(-/-) sIgM(+) cells can develop, seed the peripheral lymphoid tissues and accumulate in numbers overtime. However, these mutant B cells failed to mature and are non-responsive to BCR cross-linking in terms of proliferation and up-regulation of activation markers such as CD69 and CD86 (B7-2). In addition, the CD5(+) subset of B cells is absent. The immune response to T cell-independent antigen but not T cell-dependent antigen is also impaired. Overall, the phenotype of BLNK(-/-) mice bears a striking resemblance to that of xid mice which is the murine model of human XLA that has a mutation in Bruton's tyrosine kinase. This raises the interesting possibility that mutation in BLNK/SLP-65 may be responsible for certain human immunodeficiencies. (+info)
Anti-idiotypic antibodies in patients with different clinical forms of paracoccidioidomycosis.
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Paracoccidioidomycosis (PCM) is the most prevalent systemic mycosis in Latin America. Patients with PCM show a wide spectrum of clinical and pathological manifestations depending on both host and pathogen factors. Two clinical forms of the disease are recognized: the acute or juvenile form and the chronic or adult form. The major antigenic component of the parasite is a glycoprotein of 43 kDa (gp43). All patient sera present antibodies against gp43 (anti-gp43) and, as demonstrated before by our group, spontaneous anti-idiotypic (anti-Id) antibodies (Ab2) can be detected in patient sera with high titers of anti-gp43. Since it has been postulated that anti-Id antibodies may have a modulating function, we decided to purify and characterize anti-Id antibodies in this system. The possible correlation of Ab2 titers with different clinical forms of disease was also verified. Results showed that purified human anti-Id antibodies (human Ab2) recognized specifically the idiotype of some murine monoclonal anti-gp43 (17c and 3e) but not others (40.d7, 27a, and 8a). Spontaneous anti-Id antibodies were found in all clinical forms of disease. The majority of patients (88%, n = 8) with the acute form of PCM had high titers of Ab2. However, among patients with the multifocal chronic form of the disease, only 29% (n = 14) had high titers of Ab2; 70% (n = 10) of patients with the unifocal chronic form had low titers of Ab2. A correlation between Ab2 titers and anti-gp43 titers was observed before and during antimycotic treatment. Our results suggest that titers of anti-Id antibodies correlate with the severity of PCM in humans. (+info)
Antigen receptor signalling in apoptosis-resistant mutants of WEHI 231 cells.
(70/2060)
Ligation of membrane immunoglobulin M (mIgM) induces cell cycle arrest and apoptosis in the WEHI 231 B-lymphoma cell line. The molecular mechanisms which link receptor ligation and the nuclear events that underlie this response, have yet to be fully elucidated. Here we have examined the signals induced following mIgM cross-linking in variants of WEHI 231 that no longer undergo apoptosis in response to this stimulus. Tyrosine phosphorylation of cellular substrates in two of the variants is identical to that seen in wild-type cells but in one of the mutants, VS2.12, a restricted set of substrates becomes tyrosine phosphorylated. In a second variant (E8), mIgM cross-linking does not induce elevation of intracellular Ca2+, although tyrosine phosphorylation of PLCgamma2 is induced to an equivalent extent to that seen in WEHI 231 cells. A third variant, 2E10.F9, is resistant to apoptosis despite the fact that all signals analysed appear to be similar to those induced in wild-type cells. Our findings show that resistance to apoptosis can arise as a result of mutations affecting discrete stages of the mIgM signalling pathway. The mutant lines reported here show defects that have not yet been identified in previous studies and are likely to be useful tools in dissecting the signalling of cell death in B lymphocytes. (+info)
Salivary film expresses a complex, macromolecular binding site for Streptococcus sanguis.
(71/2060)
Teeth in the oral cavity are coated with a salivary film or pellicle, which lacks apparent intermolecular organization. This heterogeneous film facilitates binding of early commensal colonizing bacteria, including Streptococcus sanguis. To test the hypothesis that sufficient intermolecular organization exists in salivary films to form binding sites for S. sanguis, an in vitro model of saliva-coated teeth was probed with murine anti-idiotypical monoclonal antibodies (mAb2, anti-ids). The anti-ids were harvested from hybridomas that were developed in response to first generation murine hybridomas that produced anti-S. sanguis adhesin monoclonal antibodies (mAb1). The anti-ids (i) reacted with experimental salivary films and inhibited S. sanguis adhesion in a dose-dependent fashion. In Western blots, the anti-ids (ii) recognized a high molecular weight salivary antigen and (iii) secretory IgA (sIgA) light chain and alpha-amylase. After isolation by gel filtration from whole saliva or mixed secretory IgA and alpha-amylase, the high molecular weight component, containing amylase activity and sIgA, bound to hydroxyapatite to promote adhesion of S. sanguis. Therefore, a complex enriched in secretory immunoglobulin A and alpha-amylase forms a S. sanguis-binding site. (+info)
IgA-lambda/IgG-kappa biclonal myeloma in which two clones proliferated in individual sites.
(72/2060)
A 72-year-old man was admitted to our hospital because of lumbago and numbness of legs. Tumor invasion at the fourth lumbar vertebra was revealed. Immunohistochemistry using specific antibodies against each heavy and light chain of immunoglobulin revealed that the myeloma cells in bone marrow were all IgA-lambda type whereas they were all positive for IgG-kappa type in a tumor of the fourth lumbar vertebra. These data indicate that the patient had IgG-kappa/IgA-lambda biclonal myeloma. Different phenotypes of M-proteins and distinct proliferating sites for two clones suggest that they may have resulted from two independent transforming events. (+info)