Deleting LAG-3 Accelerates Cardiac Allograft Rejection and Augments T Cell Memory in Mice.

J. Erfe,^1,2 C. Yang,¹ D. Ndishabandi,¹ I. Rosales,¹ R. White,¹ P. Russell,¹ R. Colvin,¹ J. Madsen,¹ A. Alessandrini.¹

¹Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA
²Yale School of Medicine, New Haven, CT

Meeting: 2017 American Transplant Congress

Abstract number: B7

Keywords: Graft survival, Heart, knockout, Mice, T cells

Session Information

Session Name: Poster Session B: Acute and Chronic Rejection

Session Type: Poster Session

Date: Sunday, April 30, 2017

Session Time: 6:00pm-7:00pm

Presentation Time: 6:00pm-7:00pm

Location: Hall D1

Purpose: Lymphocyte Activation Gene-3 (LAG-3) expresses a transmembrane receptor on activated immune cells such as T cells, NK cells, and plasmacytoid dendritic cells. It is involved in effector and regulatory functions. Here we examine the effects of blocking the LAG-3 pathway on cardiac allograft rejection.

Methods: DBA/2 donors (H2-d) cardiac allografts were transplanted without immunosuppression into C57BL/6 wild-type (WT) controls, LAG-3^-/- (KO) on a C57BL/6 background, and C57BL/6 treated with LAG-3 neutralizing antibody. Memory T-cell secretion of IFN-g to DBA/2 antigens was assessed via ELISPOT.

Results: Allografts in WT recipients rejected on average in 8.1 days. Allografts in LAG-3^-/- KO recipients rejected on average in 6.3 days (p=0.03*). Antibody-treated recipients rejected on average in 7.0 days (p=0.27). IFN-g secretion by LAG-3^-/- KO splenic T cells was on average 2.6-fold higher than WT T cells across all time points (p=0.005**, Table 1). Rejected allografts in LAG-3^-/- KO recipients showed focused endothelial lymphocytic infiltration that was magnified at 1 week post-rejection (Figure 1).

Table 1. Antigen-Specific Increased Memory T-Cell IFN-g Response

	KO/WT Ratio	Mann-Whitney U Test (KO vs. WT)
1-3 Days	2.7	P=0.05*
1 Week	1.6	P=0.10
4 Weeks	2.8	P=0.05*
Total	2.4	P=0.005**

*5% level significance

**1% level significance

Figure 1. H&E Comparison of WT and KO GraftsAt 1 week post-rejection, WT recipients show diffuse intercellular infiltration with patent vessels (A) while LAG-3^-/-KO recipients show lymphocytic infiltration of endothelium and vascular collapse (white arrow) (B). H&E, 40x.

Conclusions: The absence of LAG-3 leads to slightly faster allograft rejection, with an increase in the T-cell memory response to donor antigen. These findings suggest that maintenance of surface LAG-3 protects H-2 mismatched cardiac allografts and could be an important target for immunosuppressive therapy.

CITATION INFORMATION: Erfe J, Yang C, Ndishabandi D, Rosales I, White R, Russell P, Colvin R, Madsen J, Alessandrini A. Deleting LAG-3 Accelerates Cardiac Allograft Rejection and Augments T Cell Memory in Mice. Am J Transplant. 2017;17 (suppl 3).

To cite this abstract in AMA style:

Erfe J, Yang C, Ndishabandi D, Rosales I, White R, Russell P, Colvin R, Madsen J, Alessandrini A. Deleting LAG-3 Accelerates Cardiac Allograft Rejection and Augments T Cell Memory in Mice. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/deleting-lag-3-accelerates-cardiac-allograft-rejection-and-augments-t-cell-memory-in-mice/. Accessed November 22, 2024.

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