This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have initiated the renal transplants planned for this study. In order to develop a clinically translatable regimen our previous regimen (Nat. Med. 2009;15:746-9) was modified: CTLA-4-Ig was replaced with the higher affinity belatacept. Alefacept was increased from 0.3mg/kg to 1.0mg/kg based on in vitro and in vivo studies, and sirolimus was delivered via intramuscular injection to better approximate clinical levels. Specific pathogen free rhesus monkeys (n=5) underwent MHC mismatched renal allotransplantation. Alefacept (1mg/kg) was given on days -1, 3, 7, and weekly for 8 weeks. Belatacept (10mg/kg) was given on days -1, 3, 7 and weekly (5mg/kg) for 24 weeks. Sirolimus was given daily to maintain a trough of 6-10ng/mL for 16 weeks. The regimen successfully prevented rejection in all 5 animals. Only after both alefacept and sirolimus were weaned did any animal show evidence of rejection. Flow cytometry was used to quantify and characterize T cell subsets. Alefacept induced a transient depletion of memory T cells - most notably CD8+ TEM cells. The proportion of CD2hi T cells dramatically diminished during alefacept treatment and returned to baseline after withdrawal, suggesting that alefacept selectively targeted those cells with the highest CD2 expression. Though this regimen did not produce tolerance, these data support belatacept, alefacept, and sirolimus as a translatable, CNI and steroid-sparing regimen for human kidney transplantation. We now are investigating Modified Vaccinia Virus Ankara strain vaccination as a means of inducing a tractable viral-specific T cell response to assess the effect of this regimen of protective immunity.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
2P51RR000165-51
Application #
8357527
Study Section
Special Emphasis Panel (ZRR1-CM-5 (01))
Project Start
2011-08-01
Project End
2012-04-30
Budget Start
2011-08-01
Budget End
2012-04-30
Support Year
51
Fiscal Year
2011
Total Cost
$32,906
Indirect Cost
Name
Emory University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Maddox, S A; Kilaru, V; Shin, J et al. (2017) Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD. Mol Psychiatry :
Banerjee, Sunayana B; Gutzeit, Vanessa A; Baman, Justin et al. (2017) Perineuronal Nets in the Adult Sensory Cortex Are Necessary for Fear Learning. Neuron 95:169-179.e3
Bruner, Emiliano; Preuss, Todd M; Chen, Xu et al. (2017) Evidence for expansion of the precuneus in human evolution. Brain Struct Funct 222:1053-1060
Chen, Guiqin; Nie, Shuke; Han, Chao et al. (2017) Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats. Front Neurosci 11:112
Dehkharghani, S; Fleischer, C C; Qiu, D et al. (2017) Cerebral Temperature Dysregulation: MR Thermographic Monitoring in a Nonhuman Primate Study of Acute Ischemic Stroke. AJNR Am J Neuroradiol 38:712-720
Walker, Lary C; Jucker, Mathias (2017) The Exceptional Vulnerability of Humans to Alzheimer's Disease. Trends Mol Med 23:534-545
Payne, Christa; Cirilli, Laetitia; Bachevalier, Jocelyne (2017) An MRI study of the corpus callosum in monkeys: Developmental trajectories and effects of neonatal hippocampal and amygdala lesions. Dev Psychobiol 59:495-506
Tedesco, Dana; Thapa, Manoj; Gumber, Sanjeev et al. (2017) CD4(+) Foxp3(+) T cells promote aberrant immunoglobulin G production and maintain CD8(+) T-cell suppression during chronic liver disease. Hepatology 65:661-677
Hecht, E E; Mahovetz, L M; Preuss, T M et al. (2017) A neuroanatomical predictor of mirror self-recognition in chimpanzees. Soc Cogn Affect Neurosci 12:37-48
Fonseca, Jairo A; McCaffery, Jessica N; Kashentseva, Elena et al. (2017) A prime-boost immunization regimen based on a simian adenovirus 36 vectored multi-stage malaria vaccine induces protective immunity in mice. Vaccine 35:3239-3248

Showing the most recent 10 out of 880 publications