Nonhuman primates (NHPs) continue to serve as powerful animal models for exploring the pathogenesis of infectious and noninfectious diseases, and for testing of new therapies and vaccines that cannot be evaluated in small animal models. Over the past decade, the number of NIH-funded research projects employing NHPs has increased by 50%. However, in the absence of readily available transgenic or gene knock-out primates, the utility of the NHP models is often limited by the availability of reagents capable of in vivo modulation of specific immune functions. In the preceding funding periods, this grant established the NIH Nonhuman Primate Reagent Resource, a program for developing and distributing antibody-based reagents that deplete specific lymphocyte subpopulations or target specific immune functions in vivo. In the past three years, this program has developed methods for generating and producing rhesus recombinant monoclonal antibodies with reduced immunogenicity and improved pharmacokinetics. Over this period, we distributed nearly 200 grams of antibody reagents supporting 48 NIH grants or intramural programs representing 8 NIH institutes or centers, and 11 non-NIH-funded programs. Furthermore, the technologies developed through this grant are also being utilized by an NIAID reagent contract which further supports investigators who use NHP models. As the need for these unique reagents continues to grow, new methods in protein engineering and expression are also emerging that will allow us to develop engineered antibodies with more focused targeting of cell subpopulations, defined effector function, and to produce them using more efficient expression methods. To continue support of NHP models across multidisciplinary scientific programs we will: 1. Develop """"""""next generation"""""""", engineered antibodies for targeting and depleting the major lymphocyte subsets in NHP 2. Engineer antibody Fc regions to modulate effector function 3. Generate fully rhesus monoclonal antibodies and explore the diversity of rhesus IgG 4. Produce IgG expression vectors for baboon, African green monkey and marmoset to enable production of recombinant antibodies for use in these other NHP species 5. Continue to produce and distribute these reagents to investigators using NHP models

Public Health Relevance

(provided by applicant): This program will facilitate better utilization of nonhuman primate models by developing and distributing unique research reagents, and support biomedical research across a wide range of scientific disciplines.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Resource-Related Research Projects (R24)
Project #
5R24RR016001-11
Application #
8105257
Study Section
Special Emphasis Panel (ZRR1-CM-6 (01))
Program Officer
O'Neill, Raymond R
Project Start
2000-09-01
Project End
2015-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
11
Fiscal Year
2011
Total Cost
$695,728
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Lakritz, Jessica R; Thibault, Derek M; Robinson, Jake A et al. (2016) ?4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy. Am J Pathol 186:1754-1761
Martinez-Murillo, Paola; Pramanik, Lotta; Sundling, Christopher et al. (2016) CD138 and CD31 Double-Positive Cells Comprise the Functional Antibody-Secreting Plasma Cell Compartment in Primate Bone Marrow. Front Immunol 7:242
Li, Shengbin; Folkvord, Joy M; Rakasz, Eva G et al. (2016) Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8+ Cells In Vivo. J Virol 90:11168-11180
Lakritz, Jessica R; Robinson, Jake A; Polydefkis, Michael J et al. (2015) Loss of intraepidermal nerve fiber density during SIV peripheral neuropathy is mediated by monocyte activation and elevated monocyte chemotactic proteins. J Neuroinflammation 12:237
Nowlin, Brian T; Burdo, Tricia H; Midkiff, Cecily C et al. (2015) SIV encephalitis lesions are composed of CD163(+) macrophages present in the central nervous system during early SIV infection and SIV-positive macrophages recruited terminally with AIDS. Am J Pathol 185:1649-65
Saunders, Kevin O; Pegu, Amarendra; Georgiev, Ivelin S et al. (2015) Sustained Delivery of a Broadly Neutralizing Antibody in Nonhuman Primates Confers Long-Term Protection against Simian/Human Immunodeficiency Virus Infection. J Virol 89:5895-903
Saunders, Kevin O; Wang, Lingshu; Joyce, M Gordon et al. (2015) Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection. J Virol 89:8334-45
Lakritz, Jessica R; Bodair, Ayman; Shah, Neal et al. (2015) Monocyte Traffic, Dorsal Root Ganglion Histopathology, and Loss of Intraepidermal Nerve Fiber Density in SIV Peripheral Neuropathy. Am J Pathol 185:1912-23
Soulas, Caroline; Autissier, Patrick J; Burdo, Tricia H et al. (2015) Distinct phenotype, longitudinal changes of numbers and cell-associated virus in blood dendritic cells in SIV-infected CD8-lymphocyte depleted macaques. PLoS One 10:e0119764
Connick, Elizabeth; Folkvord, Joy M; Lind, Katherine T et al. (2014) Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL. J Immunol 193:5613-25

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