Overexpression of Fibrinogen-Like Protein 2 Promotes Tolerance in a Fully Mismatched Murine Model of Heart Transplantation

A. Bartczak, A. Chruscinski, M. Mendicino, H. Liu, J. Zhang, W. He, A. Z. Amir, A. Nguyen, R. Khattar, H. Sadozai, C. G. Lobe, O. Adeyi, M. J. Phillips, L. Zhang, R. M. Gorczynski, D. Grant, G. A. Levy

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Fibrinogen-like protein 2 (FGL2) is an immunomodulatory protein that is expressed by regulatory T cells (Tregs). The objective of this study was to determine if recombinant FGL2 (rFGL2) treatment or constitutive FGL2 overexpression could promote transplant tolerance in mice. Although rFGL2 treatment prevented rejection of fully mismatched cardiac allografts, all grafts were rejected after stopping treatment. Next, we generated FGL2 transgenic mice (fgl2 Tg ) that ubiquitously overexpressed FGL2. These mice developed normally and had no evidence of the autoimmune glomerulonephritis seen in fgl2 −/− mice. Immune characterization showed fgl2 Tg T cells were hypoproliferative to stimulation with alloantigens or anti-CD3 and anti-CD28 stimulation, and fgl2 Tg Tregs had increased immunosuppressive activity compared with fgl2 +/+ Tregs. To determine if FGL2 overexpression can promote tolerance, we transplanted fully mismatched cardiac allografts into fgl2 Tg recipients. Fifty percent of cardiac grafts were accepted indefinitely in fgl2 Tg recipients without any immunosuppression. Tolerant fgl2 Tg grafts had increased numbers and proportions of Tregs and tolerant fgl2 Tg mice had reduced proliferation to donor but not third party antigens. These data show that tolerance in fgl2 Tg recipients involves changes in Treg and T cell activity that contribute to a higher intragraft Treg–to–T cell ratio and acceptance of fully mismatched allografts.

Original languageEnglish (US)
Pages (from-to)1739-1750
Number of pages12
JournalAmerican Journal of Transplantation
Volume16
Issue number6
DOIs
StatePublished - Jan 1 2016

Fingerprint

Heart Transplantation
Fibrinogen
Transgenic Mice
Proteins
Allografts
Transplants
Regulatory T-Lymphocytes
T-Lymphocytes
Isoantigens
Immunosuppressive Agents
Glomerulonephritis
Immunosuppression
Therapeutics
Antigens

Cite this

Overexpression of Fibrinogen-Like Protein 2 Promotes Tolerance in a Fully Mismatched Murine Model of Heart Transplantation. / Bartczak, A.; Chruscinski, A.; Mendicino, M.; Liu, H.; Zhang, J.; He, W.; Amir, A. Z.; Nguyen, A.; Khattar, R.; Sadozai, H.; Lobe, C. G.; Adeyi, O.; Phillips, M. J.; Zhang, L.; Gorczynski, R. M.; Grant, D.; Levy, G. A.

In: American Journal of Transplantation, Vol. 16, No. 6, 01.01.2016, p. 1739-1750.

Research output: Contribution to journalArticle

Bartczak, A, Chruscinski, A, Mendicino, M, Liu, H, Zhang, J, He, W, Amir, AZ, Nguyen, A, Khattar, R, Sadozai, H, Lobe, CG, Adeyi, O, Phillips, MJ, Zhang, L, Gorczynski, RM, Grant, D & Levy, GA 2016, 'Overexpression of Fibrinogen-Like Protein 2 Promotes Tolerance in a Fully Mismatched Murine Model of Heart Transplantation', American Journal of Transplantation, vol. 16, no. 6, pp. 1739-1750. https://doi.org/10.1111/ajt.13696
Bartczak, A. ; Chruscinski, A. ; Mendicino, M. ; Liu, H. ; Zhang, J. ; He, W. ; Amir, A. Z. ; Nguyen, A. ; Khattar, R. ; Sadozai, H. ; Lobe, C. G. ; Adeyi, O. ; Phillips, M. J. ; Zhang, L. ; Gorczynski, R. M. ; Grant, D. ; Levy, G. A. / Overexpression of Fibrinogen-Like Protein 2 Promotes Tolerance in a Fully Mismatched Murine Model of Heart Transplantation. In: American Journal of Transplantation. 2016 ; Vol. 16, No. 6. pp. 1739-1750.
@article{f6a8ec277a154f3299f055dae50cc466,
title = "Overexpression of Fibrinogen-Like Protein 2 Promotes Tolerance in a Fully Mismatched Murine Model of Heart Transplantation",
abstract = "Fibrinogen-like protein 2 (FGL2) is an immunomodulatory protein that is expressed by regulatory T cells (Tregs). The objective of this study was to determine if recombinant FGL2 (rFGL2) treatment or constitutive FGL2 overexpression could promote transplant tolerance in mice. Although rFGL2 treatment prevented rejection of fully mismatched cardiac allografts, all grafts were rejected after stopping treatment. Next, we generated FGL2 transgenic mice (fgl2 Tg ) that ubiquitously overexpressed FGL2. These mice developed normally and had no evidence of the autoimmune glomerulonephritis seen in fgl2 −/− mice. Immune characterization showed fgl2 Tg T cells were hypoproliferative to stimulation with alloantigens or anti-CD3 and anti-CD28 stimulation, and fgl2 Tg Tregs had increased immunosuppressive activity compared with fgl2 +/+ Tregs. To determine if FGL2 overexpression can promote tolerance, we transplanted fully mismatched cardiac allografts into fgl2 Tg recipients. Fifty percent of cardiac grafts were accepted indefinitely in fgl2 Tg recipients without any immunosuppression. Tolerant fgl2 Tg grafts had increased numbers and proportions of Tregs and tolerant fgl2 Tg mice had reduced proliferation to donor but not third party antigens. These data show that tolerance in fgl2 Tg recipients involves changes in Treg and T cell activity that contribute to a higher intragraft Treg–to–T cell ratio and acceptance of fully mismatched allografts.",
author = "A. Bartczak and A. Chruscinski and M. Mendicino and H. Liu and J. Zhang and W. He and Amir, {A. Z.} and A. Nguyen and R. Khattar and H. Sadozai and Lobe, {C. G.} and O. Adeyi and Phillips, {M. J.} and L. Zhang and Gorczynski, {R. M.} and D. Grant and Levy, {G. A.}",
year = "2016",
month = "1",
day = "1",
doi = "10.1111/ajt.13696",
language = "English (US)",
volume = "16",
pages = "1739--1750",
journal = "American Journal of Transplantation",
issn = "1600-6135",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Overexpression of Fibrinogen-Like Protein 2 Promotes Tolerance in a Fully Mismatched Murine Model of Heart Transplantation

AU - Bartczak, A.

AU - Chruscinski, A.

AU - Mendicino, M.

AU - Liu, H.

AU - Zhang, J.

AU - He, W.

AU - Amir, A. Z.

AU - Nguyen, A.

AU - Khattar, R.

AU - Sadozai, H.

AU - Lobe, C. G.

AU - Adeyi, O.

AU - Phillips, M. J.

AU - Zhang, L.

AU - Gorczynski, R. M.

AU - Grant, D.

AU - Levy, G. A.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Fibrinogen-like protein 2 (FGL2) is an immunomodulatory protein that is expressed by regulatory T cells (Tregs). The objective of this study was to determine if recombinant FGL2 (rFGL2) treatment or constitutive FGL2 overexpression could promote transplant tolerance in mice. Although rFGL2 treatment prevented rejection of fully mismatched cardiac allografts, all grafts were rejected after stopping treatment. Next, we generated FGL2 transgenic mice (fgl2 Tg ) that ubiquitously overexpressed FGL2. These mice developed normally and had no evidence of the autoimmune glomerulonephritis seen in fgl2 −/− mice. Immune characterization showed fgl2 Tg T cells were hypoproliferative to stimulation with alloantigens or anti-CD3 and anti-CD28 stimulation, and fgl2 Tg Tregs had increased immunosuppressive activity compared with fgl2 +/+ Tregs. To determine if FGL2 overexpression can promote tolerance, we transplanted fully mismatched cardiac allografts into fgl2 Tg recipients. Fifty percent of cardiac grafts were accepted indefinitely in fgl2 Tg recipients without any immunosuppression. Tolerant fgl2 Tg grafts had increased numbers and proportions of Tregs and tolerant fgl2 Tg mice had reduced proliferation to donor but not third party antigens. These data show that tolerance in fgl2 Tg recipients involves changes in Treg and T cell activity that contribute to a higher intragraft Treg–to–T cell ratio and acceptance of fully mismatched allografts.

AB - Fibrinogen-like protein 2 (FGL2) is an immunomodulatory protein that is expressed by regulatory T cells (Tregs). The objective of this study was to determine if recombinant FGL2 (rFGL2) treatment or constitutive FGL2 overexpression could promote transplant tolerance in mice. Although rFGL2 treatment prevented rejection of fully mismatched cardiac allografts, all grafts were rejected after stopping treatment. Next, we generated FGL2 transgenic mice (fgl2 Tg ) that ubiquitously overexpressed FGL2. These mice developed normally and had no evidence of the autoimmune glomerulonephritis seen in fgl2 −/− mice. Immune characterization showed fgl2 Tg T cells were hypoproliferative to stimulation with alloantigens or anti-CD3 and anti-CD28 stimulation, and fgl2 Tg Tregs had increased immunosuppressive activity compared with fgl2 +/+ Tregs. To determine if FGL2 overexpression can promote tolerance, we transplanted fully mismatched cardiac allografts into fgl2 Tg recipients. Fifty percent of cardiac grafts were accepted indefinitely in fgl2 Tg recipients without any immunosuppression. Tolerant fgl2 Tg grafts had increased numbers and proportions of Tregs and tolerant fgl2 Tg mice had reduced proliferation to donor but not third party antigens. These data show that tolerance in fgl2 Tg recipients involves changes in Treg and T cell activity that contribute to a higher intragraft Treg–to–T cell ratio and acceptance of fully mismatched allografts.

UR - http://www.scopus.com/inward/record.url?scp=84978823386&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978823386&partnerID=8YFLogxK

U2 - 10.1111/ajt.13696

DO - 10.1111/ajt.13696

M3 - Article

VL - 16

SP - 1739

EP - 1750

JO - American Journal of Transplantation

JF - American Journal of Transplantation

SN - 1600-6135

IS - 6

ER -