PubMed · 8047118
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1994-08-04. Replication defined.. https://doi.org/10.1038/370314a0
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Murine OKT3 monoclonal antibodies function as an immunosuppressant drug for organ transplant recipients. A contraindication to retreatment may develop, however, because a high proportion of OKT3-treated patients form anti-OKT3 antibodies. Previous data have shown that only antiidiotypic IgG antibodies can negate the beneficial effect of the drug. Eighty-two OKT3-treated transplanted patients were tested by ELISA for IgG, IgK and IgA anti-OKT3 antibodies and compared with 200 controls. The anti-OKT3 antibody-positive sera were screened additionally by flow cytometry for the presence of antiidiotypic activity by measuring Ortho OKT3-FITC activity on a CD3-positive cell line, Jurkat, before and after incubation with serial dilutions of patient and control sera. Forty-four of 82 patients developed antibodies to OKT3, 20 manifested IgG, 20 produced both IgG and IgA, and 4 IgA only. We never detected IgM anti-OKT3. Of the 44 anti-OKT3-positive patient sera, 25 showed antiidiotypic specificity. Two IgG/IgA anti-OKT3-positive patient sera were IgG-depleted by Protein G. Both continued to exhibit antiidiotypic IgA activity. IgA anti-OKT3 was associated with low serum OKT3 levels and lack of ability of OKT3 to lower total CD3 cell numbers to therapeutic levels. This is the first report of IgA anti-OKT3 antibody in transplant recipients. Isotype IgA anti-OKT3 was observed in 54% of the patients whose sera tested positive for anti-OM by ELISA. The IgG/ IgA anti-OKT3-positive patient sera tested continued to exhibit antiidiotypic OKT3 reactivity when depleted of IgG. We urge that OKT3-treated patients be monitored routinely for IgA anti-OKT3 antibodies to avoid the expense and potential complications of retreatment with this drug in sensitized patients.
The antigen receptors on T and B lymphocytes can transduce both agonist and antagonist signals leading either to activation/survival or anergy/death. The outcome of B lymphocyte antigen receptor (BCR) triggering depends upon multiple parameters which include (a) antigen concentration and valency, (b) duration of BCR occupancy, (c) receptor affinity, and (d) B cell differentiation stages. Herein, using anti-immunoglobulin kappa and lambda light chain antibodies, we analyzed the response of human naive, germinal center (GC) or memory B cells to BCR cross-linking regardless of heavy chain Ig isotype or intrinsic BCR specificity. We show that after CD40-activation, anti-BCR (kappa + gamma) can elicit an intracellular calcium flux on both GC and non-GC cells. However, prolonged BCR cross-linking induces death of CD40-activated GC B cells but enhances proliferation of naive or memory cells. Anti-kappa antibody only kills kappa + GC B cells without affecting surrounding gamma + GC B cells, thus demonstrating that BCR-mediated killing of GC B lymphocytes is a direct effect that does not involve a paracrine mechanism. BCR-mediated killing of CD40-activated GC B cells could be partially antagonized by the addition of IL-4. Moreover, in the presence of IL-4, prestimulation through CD40 could prevent subsequent anti-Ig-mediated cell death, suggesting a specific role of this combination in selection of GC B cells. This report provides evidence that in human, susceptibility to BCR killing is regulated along peripheral B cell differentiation pathway.
Clones expressing a partial human cytomegalovirus putative fusion receptor were selected by binding specifically to monoclonal anti-idiotypic antibodies that mimic glycoprotein H. cDNA was isolated from 2 of the clones (131 and 611) and fused in frame with the glutathione S-transferase gene in a pGEX-4T-1 vector. Two purified peptides (FR131 and FR611) were produced: both were shown to bind specifically to the monoclonal anti-idiotypic antibodies and inhibit virus/cell fusion and viral plaque formation in a specific and dose-dependent manner. This is the first demonstration of cloned peptides encoding a putative cell membrane receptor that are able to block cytomegalovirus infection.