Correlation between expression of antibodies to histone H2B and clinical activity in HIV-infected individuals.

Levels of autoantibodies specific for the histone, H2B, were measured in individuals with HIV infection. In comparison with normal (uninfected) controls, infected patients, particularly those with symptomatic disease, had significantly elevated titres of anti-H2B antibodies. Longitudinal studies confirmed that levels of these antibodies were highest in patients with lymphadenopathy and declined with the development of AIDS. In preliminary experiments designed to determine the biological significance of the anti-histone antibodies, H2B was shown to be immunologically cross-reactive with an 18-kD antigen on the surface of HIV-infected or mitogen-activated CD4+ cells. Protein sequencing of the 18-kD antigen has since shown complete homology with histone H2B. Because the titres of H2B autoantibodies were found to parallel the numbers of circulating CD4 cells, it is possible that these antibodies are involved in the destruction of the helper/inducer T lymphocyte population.

A comparison of the anti-idiotypic responses generated by antibodies to a protein and a hapten: a common interspecies idiotype on antibodies against human albumin induces an idiotypic network in rabbits.

Idiotypic networks have the capacity to exert significant influences on immune responses and an understanding of the ways to manipulate these networks may lead to new modalities in immunotherapy. In order to gain further insights into the nature of the immune responses stimulated by immunoglobulin idiotypes, rabbits were immunized with a mAb (Ab1) against a large globular protein, human albumin, or a mAb against a hapten, TNP. All rabbits developed anti-idiotypic antibodies (Ab2) and the rabbits immunized with anti-human albumin concomitantly developed antibodies to human albumin (Ab3). Ab2 prepared from these rabbits blocked binding of Ab1 to antigen and the anti-human albumin Ab2 reacted with all species of anti-human albumin including sheep, rabbit, rat and goat. The anti-TNP Ab2 reacted only with the mouse anti-TNP Ab1. This TNP Ab2 bound only to intact Ab1 whereas the human albumin Ab2 reacted with the Ab1 heavy chain. To compare the relative efficiencies of anti-idiotypic antibodies and antigen in inducing antibody, mice were immunized with rabbit Ab2 or antigen. All mice immunized with Ab2 developed anti-idiotypic Ab3, but only the human albumin Ab2 preparations elicited antigen specific Ab3; the amount of antibody produced was less than 1% of that found by immunization with antigen. The type of antibody induced in the Ab2-immunized mice was compared with that found in the antigen-immunized mice and in the Ab1-immunized rabbits. The mouse anti-albumin Ab3 was comparable to mouse Ab1 in terms of affinity and specificity for proteolytic fragments of human albumin. The Ab3 which arose in Ab1-immunized rabbits had a higher affinity and broader epitope specificity and was similar to antibodies raised against antigen. These results show considerable differences in the ability of similar anti-idiotypic antibodies to induce immune responses as well as considerable differences in the nature of a response seen within an intact network compared to an artificially induced network.

Common epitope on HIV p24 and human platelets.

Mimicry of human antigen by HIV may underlie the autoreactivity seen in AIDS. A mouse monoclonal antibody (VIC8) raised against HIV p24 cross-reacted with human platelets; binding could be abolished by recombinant p24 antigen. VIC8 bound less well to platelets from patients with HIV than to those from healthy individuals. In the HIV group, binding was not related to p24 antigenaemia, disease stage, or platelet counts. This cross-reactivity is another example of antigenic mimicry by HIV and may be mechanistically important in HIV-associated autoimmune-like thrombocytopenia.

Patterns of corneal graft rejection in the rabbit and reversal of rejection with monoclonal antibodies.

The purpose of this study was to determine whether the local administration of monoclonal antibodies could reverse rabbit corneal graft rejection. To provide a rational basis for the choice of monoclonal antibodies as potential immunosuppressive agents, the phenotypes of cells infiltrating rejecting rabbit corneal allografts were examined by immunohistochemistry. About half the leukocytes accumulating in these grafts bore an immunodominant T cell marker, over two-thirds carried MHC class II antigens, and about one-fifth carried myeloid cell markers. A kinetic study of the cell population appearing in rabbit aqueous during corneal graft rejection was performed by examination of repetitive anterior chamber taps taken over a ten-day period; again, the major components were T cells, MHC class II antigen-positive cells and myeloid cells. Monoclonal antibodies L11/135 (directed against a peripheral T cell determinant), 2C4 (directed against a monomorphic MHC class II antigen), and LION 2 (directed against a myeloid antigen) were chosen for intracameral injection into rabbits with rejecting corneal grafts. Each animal received a total of 50-100 micrograms of antibody in two injections at 3-4-day intervals. L11/135 and LION 2 reversed rejection in 5/9 and 8/12 animals, respectively, in the absence of any other immunosuppression; 2C4 was without effect. We suggest that monoclonal antibody therapy in corneal transplantation deserves further attention.

Production of a polyspecific human monoclonal antibody reacting with an epidermal antigen.

A clone of cells secreting an antibody to an epidermal antigen was generated from a patient with a blistering skin lesion. Although produced by fusion of human lymphocytes to a HAT-sensitive myeloma, this clone of cells did not have characteristics of a hybridoma. A true hybridoma was produced by fusion of this clone to a HATr/ouabain(r) myeloma line. The IgM antibody secreted by this clone reacted with the intercellular region of the epidermis of normal human skin in a manner similar to pemphigus autoantibodies. In addition, in normal human kidney the antibody bound to glomeruli and tubules. It also reacted with an antigen present in the cytoplasm of a wide variety of cell lines including epithelial, lymphoid and myeloid types. No reaction was found with the surface of any of the cell lines, nor with DNA or phospholipid antigens. This monoclonal antibody may define an autoantibody specificity which mediates some autoimmune skin lesions. Its polyspecificity is reminiscent of some other human hybridoma autoantibodies, and its reaction with components of the kidney suggests an alternative pathology for renal disease in such patients.