Rabbits are the only or best animal model for several infectious diseases. The sequence of the rabbit genome at 7x coverage was completed in July 2008 at Broad Institute MIT and Harvard. Assembly of the deep coverage was submitted to GenBank (accession AAGW02000000) on August 3, 2009. The sequences we have been able to find and use in the incomplete 2x trace archive and assembly along with the 7x trace archive have already proven useful for various studies. Two websites are now available:the first is by NIAID on Rabbit in Immunology &Infectious Disease(http://www3.niaid.nih.gov/research/resources/ri/. This site offers a summary of an NIAID workshop on Rabbit Models of Human Infectious diseases held in 2005. The second site is one maintained by the National Center for Biotechnology Information (NCBI), www.ncbi.nlm.nih.gov/projects/genome/guide/rabbit/.Rabbits of the b9 allotype have been used in a variety of immunization projects where highly specific high affinity antibodies are desired. The conserved N-heptad repeat (NHR) region of gp41of HIV-1 forms a coiled-coil that is a precursor to the fusion reaction. HIV-1-neutralizing monoclonal antibodies were isolated from immune phage display libraries from rabbits of b9 allotype immunized with a mimetic of the NHR coiled-coil, (N35CCG-N13) of the NHR region of gp41. The VDJ sequences of the three recovered neutralizing scFv from one rabbit were clonally related and had a heavy chain variable region (VH) encoded by a rarely expressed VH gene (x32) (Nelson et al. 2008).Immunization of b9 rabbits also led to mAbs specific for NgR1 and NgR2 that were used for characterization of a novel antagonist of CNS myelin inhibition (Robak et al, 2009). Our published work to develop a rabbit model of SLE (Puliyath et al, 2008, and reference therein) has a raised interest in the use of rabbits selectively bred to produce autoantibodies for studies aimed at development of new vaccines to elicit broadly neutralizing anti-HIV responses. It has been hypothesized that B-cells encoding antibodies capable of broadly neutralizing different HIV strains are selected against during B-cell development due to potential autoantibody activity. It is also known that BAFF-mediated survival of immature B cells contributes to the survival and maturation of autoreactive B cells. The responses to various antigens that may elicit broadly neutralizing antibodies to HIV will be or are currently being investigated by several groups using relatives of the pedigreed rabbits reported in our previous studies because they are more likely to produce autoantibodies. The plan of one study in progress also includes use of recombinant rabbit BAFF that we described (Yang et al. 2009). In more recent studies, a chimeric rabbit/human Fab library generated from immunized rabbits, of b9 allotype was screened to identify chimeric rabbit/human Fab of high affinity and specificity for a native epitope of the Rev protein of HIV-1. We hypothesized that chimeric rabbit/human Fab could facilitate co-crystallization. By binding to a unique epitope, the Fab was shown to potently dissolve Rev polymers. Fab/Rev complexes were purified, characterized and crystallized. The ability to serve as crystal chaperones is a new application of broad utility for chimeric rabbit/human Fab. The selected mAb from b9 rabbit immunization also had a heavy chain variable region encoded by an unusual VH gene. (Ms in preparation S. Stahl, N.Watts, P.Wingfield, et al. PEB. NIAMS, R Mage, NIAID, C. Rader NCI).
|Stahl, Stephen J; Watts, Norman R; Rader, Christoph et al. (2010) Generation and characterization of a chimeric rabbit/human Fab for co-crystallization of HIV-1 Rev. J Mol Biol 397:697-708|
|Robak, Laurie A; Venkatesh, Karthik; Lee, Hakjoo et al. (2009) Molecular basis of the interactions of the Nogo-66 receptor and its homolog NgR2 with myelin-associated glycoprotein: development of NgROMNI-Fc, a novel antagonist of CNS myelin inhibition. J Neurosci 29:5768-83|
|Yang, Jiahui; Pospisil, Richard; Ray, Satyajit et al. (2009) Investigations of a rabbit (Oryctolagus cuniculus) model of systemic lupus erythematosus (SLE), BAFF and its receptors. PLoS One 4:e8494|
|Pospisil, Richard; Kabat, Juraj; Mage, Rose G (2009) Characterization of rabbit CD5 isoforms. Mol Immunol 46:2456-64|
|Yang, Jiahui; Pospisil, Richard; Mage, Rose G (2009) Expression and localization of rabbit B-cell activating factor (BAFF) and its specific receptor BR3 in cells and tissues of the rabbit immune system. Dev Comp Immunol 33:697-708|
|Puliyath, Nandakumar; Ray, Satyajit; Milton, Jacqueline et al. (2008) Genetic contributions to the autoantibody profile in a rabbit model of Systemic Lupus Erythematosus (SLE). Vet Immunol Immunopathol 125:251-67|
|Nelson, Josh D; Kinkead, Heather; Brunel, Florence M et al. (2008) Antibody elicited against the gp41 N-heptad repeat (NHR) coiled-coil can neutralize HIV-1 with modest potency but non-neutralizing antibodies also bind to NHR mimetics. Virology 377:170-83|