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Antigen Immune Responses to Lcrv, A An Age-Old Paradigm Challenged: Old Baboons Generate Vigorous Humoral Immune Responses to LcrV, A Plague Antigen This information is current as of September 27, 2021. Sue Stacy, Amanda Pasquali, Valerie L. Sexton, Angelene M. Cantwell, Ellen Kraig and Peter H. Dube J Immunol 2008; 181:109-115; ; doi: 10.4049/jimmunol.181.1.109 http://www.jimmunol.org/content/181/1/109 Downloaded from References This article cites 44 articles, 6 of which you can access for free at: http://www.jimmunol.org/content/181/1/109.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology An Age-Old Paradigm Challenged: Old Baboons Generate Vigorous Humoral Immune Responses to LcrV, A Plague Antigen1 Sue Stacy,*‡ Amanda Pasquali,* Valerie L. Sexton,† Angelene M. Cantwell,† Ellen Kraig,2*‡ and Peter H. Dube†‡ Immune senescence in the elderly results in decreased immunity with a concomitant increase in susceptibility to infection and diminished efficacy of vaccination. Nonhuman primate models have proven critical for testing of vaccines and therapeutics in the general population, but a model using old animals has not been established. Toward that end, immunity to LcrV, a protective Ag from Yersinia pestis, was tested in young and old baboons. Surprisingly, there was no age-associated loss in immune competence; LcrV elicited high-titer, protective Ab responses in the older individuals. The primary responses in the younger baboons were Downloaded from lower, but they did show boosting upon secondary immunization to the levels achieved in the old animals. The LcrV Ag was also tested in mice and, as expected, age-associated loss of immunity was seen; older animals responded with lower-titer Abs and, as a result, were more susceptible to Yersinia challenge. Thus, although age-related loss in immune function has been observed in humans, rodents, and some nonhuman primates, baboons appear to be unusual; they age without losing immune competence. The Journal of Immunology, 2008, 181: 109–115. http://www.jimmunol.org/ lderly individuals show diminished immune responses, (17–20). Similarly, the age-associated loss of immunity can be making them significantly more susceptible to infections overcome by giving multiple immunizations or higher doses of the E and cancer (reviewed in Ref. 1–4). In addition, vaccina- Ag. This further substantiates the imperative to test vaccine pro- tion protocols are typically less efficacious in the elderly and al- tocols for their effectiveness in both old and young subjects. though higher doses of immunogen may enhance the response, it Although many vaccines are first tested in rodents, this may not is typically still lower than the one elicited in younger individuals be ideal for protection studies because mice are resistant to many (5–8). Deficits in the ability of older subjects to generate immune human pathogens (like HIV) due to sequence differences in their responses, particularly to “new” Ags that they have not previously cellular receptors. Thus, many vaccine protocols for use in humans encountered, have been widely reported. In contrast, immune have been tested in nonhuman primate (NHP)3 models (21–26). by guest on September 27, 2021 memory to Ags encountered in one’s youth does survive aging and However, the vast majority of these studies have been undertaken can be recalled in old age (9–10). Given the current demographic in young or middle-aged NHPs and none of these primate models composition in the U.S., the numbers of aging individuals will has been validated for use in testing vaccines for efficacy in older continue to grow and they already comprise a significant “at risk” individuals. Thus, in the current study, the ability of young and old population. Thus, it is critically important to develop and test pro- NHPs to respond to a “new” Ag has been assessed. We chose to tocols for enhancing immunity particularly to “new” Ags in old, as focus on the baboon, Papio hamadryas, for several reasons. It is an well as in young, individuals. excellent primate model system due both to its close genetic re- Most of the research into the effects of aging on immunity has latedness (Ϸ96% DNA homology) and the similarity of its im- incorporated rodent models and, for the most part, analogous age- mune system to humans (27). For example, unlike macaques and associated deficiencies of cellular and humoral immunity have some other monkeys, baboons resemble humans and chimpanzees been seen (11–16). For example, the ability to generate an immune in exhibiting four IgG subclasses (28). Moreover, because baboons response to a “new” Ag or epitope not previously encountered is breed well in captivity, they are more readily available than some significantly diminished in older animals. In contrast, memory im- other NHPs. Baboons are being used extensively in infectious dis- munity to Ags encountered in one’s youth appears largely intact ease and vaccine studies (21, 24–25, 27) so it will be important to assess the effects of aging on this NHP model. It has been reported that serum autoantibodies in baboons increase with age, analogous *Department of Cellular and Structural Biology, †Department of Microbiology and to humans (29), but there are no studies that assess the effects of Immunology, and ‡Barshop Center for Longevity Studies, University of Texas Health aging on humoral immunity. Fortunately for this study, the South- Science Center, San Antonio, TX 78229 west National Primate Research Center in San Antonio maintains Received for publication July 27, 2007. Accepted for publication April 22, 2008. the largest colony of baboons worldwide; it consists of Ͼ3700 The costs of publication of this article were defrayed in part by the payment of page individual animals, including a geriatric cohort. charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Given that aging most dramatically affects immune responses to 1 This work was supported by funding from the Southwest National Primate Center Ags not previously encountered by the subject, it was imperative (pilot study Grant P51 RR13986), the National Institute on Aging (R03AG22675 to S.S.), and a University of Texas Health Science Center, San Antonio Presidential Research Enhancement Fund grant. 3 Abbreviations used in this paper: NHP, Nonhuman primate; TTFC, Tetanus toxoid 2 Address correspondence and reprint requests to Dr. Ellen Kraig, Cellular and Struc- fragment C. tural Biology MC 7762, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229. E-mail address: [email protected] Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 www.jimmunol.org 110 BABOON IMMUNE COMPETENCE IS MAINTAINED WITH AGE to select an immunogen that would elicit a primary response in the baboon colony. Thus, we chose LcrV, a protein Ag from Yersinia pestis, the causative agent of bubonic plague. Y. pestis is the most virulent bacterial pathogen currently known and in geographic ar- eas where it is endemic in rodent populations, including the south- western U.S., humans remain at risk. Any baboon that had come into contact with Y. pestis would most likely have succumbed, as the infection is typically fatal. Thus, none of the subjects used in this study were likely to have had a prior exposure to this virulent bacterium and, therefore, they should respond to LcrV as a “new” Ag. Furthermore, although there is no currently licensed plague vac- cine for use in the U.S., a new subunit vaccine, which includes FIGURE 1. Preparation of protein immunogens. The recombinant pro- LcrV as one of its components, is showing promise (30–32). By teins were prepared in a prokaryotic expression system and purified, as described in Materials and Methods. In order to demonstrate purity, they incorporating LcrV in this study, we could assess both the titer of were fractionated on a SDS polyacrylamide gel and stained with Coomas- reactive Ab produced and its ability to protect against infection. sie Blue. A duplicate gel was electrophoretically transferred and the re- This was considered a significant advantage as there is growing sulting Western blot was developed using an Ab that recognizes the vector- concern that plague may re-emerge as a significant danger to hu- encoded “his” tag. man health due to the recent identification of multidrug resistant Downloaded from strains of Y. pestis, thus, making the development of an effective vaccine a priority (33–34). Yet, in no case has a protein-based an Ab against the vector-encoded “his” tag (Qiagen) and developed using vaccine for plague been tested in older animals whose immune an alkaline phosphatase conjugated secondary Ab. responses are likely compromised. Thus, these studies will provide Baboon immunization the first data on the effects of aging on the humoral immune response The purified recombinant proteins were absorbed to 25% alum (Vol/Vol) to LcrV in two different species, mice and baboons. Moreover, al- http://www.jimmunol.org/ and used to immunize young (21⁄2 years) and old (19–24 years) baboons though the Y.
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