ORIGINAL PRE-CLINICAL SCIENCE
Interleukin-16 deficiency suppresses the development of
chronic rejection in murine cardiac transplantation model
Naoyuki Kimura, MD,
a
Satoshi Itoh, MD,
a
Susumu Nakae, PhD,
b
Robert C. Axtell, PhD,
c
Jeffrey B. Velotta, MD,
a
Ernst Jan Bos, BS,
a
Denis R. Merk, MD,
a
Yongquan Gong, MD,
a
Homare Okamura, MD,
a
Claude M. Nagamine, DVM, PhD,
d
Hideo Adachi, MD, PhD,
e
Hardy Kornfeld, MD,
f
Robert C. Robbins, MD,
a
and Michael P. Fischbein, MD, PhD
a
From the
a
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California; the
b
Frontier Research
Initiative, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; the
c
Department of Neurology and Neurological
Sciences; and the
d
Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California; the
e
Department of Cardiovascular Surgery, Jichi Medical University, Saitama Medical Center, Saitama, Japan; and the
f
Department of
Pulmonary, Allergy & Critical Care Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
BACKGROUND: IL-16 promotes the recruitment of various cells expressing CD4, a receptor for
IL-16. The precise role of IL-16 in transplant rejection remains unknown; therefore, the present
study investigated the contribution of IL-16 to the development of chronic rejection in heart
transplants.
METHODS: C-H-2
bm12
KhEg (H-2
bm12
) donor hearts were transplanted into (1) IL-16-deficient (IL-
16
-/-
) C57BL/6J or (b) wild type (WT) control recipients (MHC class II mismatch). Grafts were
harvested at 52 days, parenchymal rejection was assessed by the ISHLT grading system, and CAV was
examined morphometrically. Graft infiltrating cells were detected 10 and 52 days after transplantation.
Intragraft cytokine and chemokine profiles were assessed. To confirm the role of IL-16 in CAV
development, C-H-2
bm12
KhEg (H-2
bm12
) donor hearts were transplanted into C57BL/6J WT recipients
treated with (1) anti-IL-16-neutralization monoclonal antibody or (b) control immunoglobulin G. Grafts
were harvested at 52 days, and CAV was quantified morphometrically. Graft-infiltrating cells were
examined histologically.
RESULTS: Parenchymal rejection and CAV was significantly attenuated in donor hearts transplanted
into IL-16
-/-
recipient mice compared with WT controls. Donor hearts transplanted into IL-16
-/-
recipients had a significant reduction in coronary artery luminal occlusion, intima-to-media ratio, and
percentage of diseased vessels. CAV was associated with decreased donor organ inflammation, as well
as donor organ cytokine (IL-1 and IL-6) and chemokine (MCP-1 and KC) protein expression. Intimal
proliferation and inflammatory cell infiltration were significantly reduced in hearts transplanted into
recipients treated with an IL-16-neutralization antibody.
CONCLUSIONS: IL-16-deficiency reduced graft inflammatory cell recruitment, and allograft inflam-
matory cytokine and chemokine production. Therefore, IL-16 neutralization may provide a potential
target for novel therapeutic treatment for cardiac allograft rejection.
J Heart Lung Transplant 2011;30:1409 –17
© 2011 International Society for Heart and Lung Transplantation. All rights reserved.
KEYWORDS:
chronic rejection;
heart transplantation;
immunology;
cytokines;
animal model
Reprint requests: Michael P. Fischbein, MD, PhD, Department of Cardiothoracic Surgery, Stanford University School of Medicine, 300 Pasteur Dr,
CVRB MC 5407, Stanford, CA, 94305. Telephone: 650-725-3828. Fax: 650-725-3846.
E-mail address: mfischbe@stanford.edu
http://www.jhltonline.org
1053-2498/$ -see front matter © 2011 International Society for Heart and Lung Transplantation. All rights reserved.
doi:10.1016/j.healun.2011.08.017