Regulatory T Cell Infusion Can Enhance Memory T Cell and Alloantibody Responses in Lymphodepleted Nonhuman Primate Heart Allograft Recipients.
1Surgery, University of Pittsburgh, Starzl Institute, Pittsburgh, PA
2Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI
3Pathology, University of Pittsburgh, Pittsburgh, PA
4Immunology, University of Pittsburgh, Pittsburgh, PA.
Meeting: 2016 American Transplant Congress
Abstract number: 168
Keywords: Immunosuppression, Primates, T cells, Tolerance
Session Information
Session Time: 8:30am-9:30am
Presentation Time: 8:45am-9:00am
Location: Veterans Auditorium
Background:
The ability of regulatory T cells (Treg) to prolong allograft survival and promote transplant tolerance in lymphodepleted rodents is well-established. Few studies have addressed the therapeutic potential of adoptively-transferred Treg in clinically-relevant large animal models. We evaluated the impact of polyclonal Treg infusion(s) on heart allograft survival in cynomolgus monkeys.
Methods:
Ex vivo expanded CD4+CD25+CD127–Foxp3+ Treg were obtained from either normal monkeys (for 3rd party infusions) or prospective recipients (for autologous infusions). Recipients (n=9) and donors were MHC-mismatched. Recipients received either no Treg infusion (n=3), single 3rd party (n=3), single autologous (n=1), or multiple autologous Treg infusions (n=2). All recipients received anti-thymocyte globulin, short-term tacrolimus, anti-IL-6R mAb and tapered rapamycin maintenance.
Results:
Treg administration in single or multiple doses (up to 1.87 billion cells) during the first month post-transplant, resulted in inferior graft function. With no Treg infusion, graft palpation score began to decline on days 28, 35 and 53. With single Treg infusion, reductions in score were observed on days 32, 41, 53 and 53, whereas with multiple Treg infusions, reductions in score were observed on days 12 and 14. This was accompanied with significantly higher cardiac enzyme CPK-MB levels.
In all recipients, T cells were profoundly reduced. CD4+Treg:CD4+Teff ratio was skewed markedly in favor of Treg during the first month post-transplant, particularly with multiple Treg infusions. With Treg infusion, there were increased incidences of effector memory T cells, enhanced IFNγ production by CD8+T cells, elevated pro-inflammatory cytokines and increased anti-donor antibody levels. .
Conclusions:
Despite marked but transient increases in Treg relative to endogenous effector T cells in lymphodepleted NHP heart graft recipients and use of “Treg-friendly” immunosuppression, the host environment/immune effector mechanisms can perturb rather than favor the potential therapeutic efficacy of adoptively-transferred Treg.
CITATION INFORMATION: Ezzelarab M, Zhang H, Lu L, Guo H, Zahorchak A, Wiseman R, Nalesnik M, Bhama J, Cooper D, Thomson A. Regulatory T Cell Infusion Can Enhance Memory T Cell and Alloantibody Responses in Lymphodepleted Nonhuman Primate Heart Allograft Recipients. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:
Ezzelarab M, Zhang H, Lu L, Guo H, Zahorchak A, Wiseman R, Nalesnik M, Bhama J, Cooper D, Thomson A. Regulatory T Cell Infusion Can Enhance Memory T Cell and Alloantibody Responses in Lymphodepleted Nonhuman Primate Heart Allograft Recipients. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/regulatory-t-cell-infusion-can-enhance-memory-t-cell-and-alloantibody-responses-in-lymphodepleted-nonhuman-primate-heart-allograft-recipients/. Accessed May 21, 2025.« Back to 2016 American Transplant Congress