Induction of central T cell tolerance: Recombinant antibodies deliver peptides for deletion of antigen-specific CD4+8+ thymocytes

Abstract

In order to prevent or ameliorate autoimmune disease, it would be desirable to induce central tolerance to peripheral self-antigens. We have investigated whether recombinant antibodies (Ab) that deliver T cell epitopes to antigen-presenting cells (APC) in the thymus can be used to induce thymocyte deletion. Troybodies are recombinant Ab with V regions specific for APC surface molecules that have T cell epitopes genetically introduced in their C domains. When MHC class II-specific Troybodies with the k2 315 T cell epitope were injected into k2 315 -specific TCR transgenic mice, a profound deletion of CD4 + 8 + thymocytes was observed. MHC class II-specific Troybodies were 10-100-fold more efficient than non-targeting peptide Ab, and 500-fold more efficient than synthetic peptide at inducing deletion. Similar findings were observed when MHC class II-specific Troybodies with the OVA 323-339 T cell epitope were injected into OVA-specific TCR transgenic mice. Although deletion was transient after a single injection, newborn mice repeatedly injected with MHC class II-specific Troybodies for 4 weeks, had reduced antigen-specific T cells in peripheral lymphoid tissues and reduced T cell responses. These experiments suggest that Troybodies constructed to target specifically thymic APC could be useful tools for induction and maintenance of central T cell tolerance in autoimmune diseases.

Delivery of Antigen to CD40 Induces Protective Immune Responses against Tumors

“…The current two types of recombinant Ab-based vaccines differ, however, in their ability to bind to FcRs. The troybody molecule expresses a complete C region of h␥3 and binds to FcRs (28). In contrast, the vaccibody molecule lacks the C H 2 domain, and therefore the FcR binding site, and should only enter APC via their V regions.…”

Antibody-targeted vaccines

“…Recent studies with the macrophage galactose-type Ctype lectin (MGL), which is another endocytic receptor also expressed by DCs, have shown that this molecule has suppressive interactions with T cells through its binding to CD45 (van Vliet et al, 2006), and another CLR, DCAL-2, has also been shown to have immunoregulatory properties . In addition to peripheral immune suppression, APC-targeting may also be able to induce central (thymus) T-cell tolerance to peptide antigens (Schjetne et al, 2005). Finally, recent disease model studies have explored the potential of using Fc receptor targeting to deliver immunomodulatory approaches for the treatment of rheumatoid arthritis (van Vuuren et al, 2006;Wenink et al, 2006).…”

DNA Vaccines: MHC II-Targeted Vaccine Protein Produced by Transfected Muscle Fibres Induces a Local Inflammatory Cell Infiltrate in Mice

“…In pioneering studies, antigens were chemically coupled to antibodies specific for APC; such antigen-antibody conjugates were shown to enhance immune responses [13] , [14] , [15] . Later, antigens have been genetically introduced into the C regions of recombinant antibodies engineered to express APC-specific variable regions [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] . Antigens have been attached to the carboxy terminal tail of Fab fragments [16] or complete IgG [23] , approaches which have certain limitations such as monovalency [16] and bulkiness [23] .…”

“…In another strategy, 9–37 aa long antigenic peptides corresponding to T cell epitopes substitute loop regions between β-strands in the C-domain [17] , [18] , [22] , [24] . The latter strategy has the advantage that the antibody structure is basically maintained with normal half lives in vivo [20] . The drawback is that the short antigenic peptides often lack conformational determinants and are poor at stimulating B cells and antibody responses.…”