Impact of Human Mutant TGF-β1/Fc Protein On Memory and Regulatory CD4+T Cells Following Lymphodepletion in Rhesus Monkeys

H. Guo,¹ L. Lu,¹ R. Wang,² H. Abdulkerim,² R. Keith,² A. Thomson,¹ M. Ezzelarab.¹

¹Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
²MassBiologics, University of Massachusetts Medical School, Boston, MA.

Meeting: 2015 American Transplant Congress

Abstract number: 491

Keywords: Immunosuppression, Primates, Tolerance, Transforming growth factor-beta (TGF-b)

Session Information

Session Name: Concurrent Session: New Immunosuppression Strategies: Primate Models

Session Type: Concurrent Session

Date: Tuesday, May 5, 2015

Session Time: 4:00pm-5:30pm

Presentation Time: 4:24pm-4:36pm

Location: Room 119-A

Background:

Tolerance to allografts is essential to avoid chronic immunosuppression and to promote long term graft function. Transforming growth factor- β plays a key role in regulatory T cell (Treg) differentiation and regulation of peripheral tolerance. Infusion of human mutant TGF-β1/Fc fusion protein (TGF-β1/Fc) in combination with rapamycin has been shown to promote donor-specific tolerance in rodents. We evaluated the influence of a human mutant TGF-β1/Fc on T cell responses in vitro and in vivo, following lymphodepletion in nonhuman primates.

Methods:

Proliferation and phenotype of activated CD4+T cells were evaluated in the presence or absence of rapamycin and TGF-β1/Fc. Four rhesus monkeys received immunosuppression in the form of Thymoglobulin and rapamycin, without (n=2) or with (n=2) TGF-β1/Fc infusion (5mg/kg, twice a week for 4 weeks). TGF-β1/Fc pharmacokinetics in lymphodepleted monkeys was assessed. Recovery of memory T cells (Tmem) and Treg after lymphodepletion was evaluated in peripheral blood and 2ry lymphoid tissues.

Results:

TGF-β1/Fc and rapamycin synergistically reduced ki67 expression and proliferation of effector and effector Tmem significantly following CD3/CD28 activation and in response to alloactivation. No increase in CD4+CD25hiFoxp3hi Treg percentage was observed. However, in combination with IL-2, increased percentages of Treg and increased Treg to Th17 ratio were observed.

In lymphodepleted monkeys, trough levels of TGF-β1/Fc infusion were maintained at 2-7 ¯o;g/mL, and were undetectable by 45 days after infusion. With no TGF-β1/Fc infusion, rapid recovery of effector and effector Tmem to pre-depletion levels was observed by day 21 after lymphodepletion and continued to increase. In contrast, in lymphodepleted monkeys with TGF-β1/Fc infusion, the recovery of CD4+Tmem was delayed until day 56 after lymphodepletion. This was associated with higher percentages of Treg and increased Treg to Tmem ratios in peripheral blood and lymph nodes. Treg to Th17 ratio was reduced after lymphodepletion with or without TGF-β1/Fc infusion.

Conclusion:

Human TGF-β1/Fc protein infusion delays the recovery of CD4+ Tmem and promotes Treg/Tmem ratio after lymphodepletion in nonhuman primates. Combined IL-2 infusion may be essential to improve Treg to Th17 ratio after lymphodepletion.

To cite this abstract in AMA style:

Guo H, Lu L, Wang R, Abdulkerim H, Keith R, Thomson A, Ezzelarab M. Impact of Human Mutant TGF-β1/Fc Protein On Memory and Regulatory CD4+T Cells Following Lymphodepletion in Rhesus Monkeys [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/impact-of-human-mutant-tgf-1fc-protein-on-memory-and-regulatory-cd4t-cells-following-lymphodepletion-in-rhesus-monkeys/. Accessed November 21, 2024.

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