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-Inducible CXCR3-Binding Chemokines, IFN-Inducible Protein 10, Monokine Induced by IFN, and IFN-Inducible T Cell 
Chemoattractant in Human Cardiac Allografts: Association with Cardiac Allograft Vasculopathy and Acute Rejection1
* Cardiovascular Medicine and Departments of
Cardiac Surgery and
Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
Center for Immunology and Inflammatory Disease, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA; and Departments of
¶ Pathology and
|| Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
CXCR3 chemokines exert potent biological effects on both immune and
vascular cells. The dual targets suggest their important roles in
cardiac allograft vasculopathy (CAV) and rejection. Therefore, we
investigated expression of IFN-inducible protein 10 (IP-10),
IFN-inducible T cell 
chemoattractant (I-TAC), monokine induced by
IFN (Mig), and their receptor CXCR3 in consecutive endomyocardial
biopsies (n = 133) from human cardiac allografts
and corresponding normal donor hearts (n = 11)
before transplantation. Allografts, but not normal hearts, contained
IP-10, Mig, and I-TAC mRNA. Persistent elevation of IP-10 and I-TAC was
associated with CAV. Allografts with CAV had an IP-10-GAPDH ratio
3.7 ± 0.8 compared with 0.8 ± 0.2 in those without CAV
(p = 0.004). Similarly, I-TAC mRNA levels were
persistently elevated in allografts with CAV (6.7 ± 1.9 in
allografts with vs 1.5 ± 0.3 in those without CAV,
p = 0.01). In contrast, Mig mRNA was induced only
during rejection (2.4 ± 0.9 with vs 0.6 ± 0.2 without
rejection, p = 0.015). In addition, IP-10 mRNA
increased above baseline during rejection (4.1 ± 2.3 in rejecting
vs 1.8 ± 1.2 in nonrejecting biopsies, p =
0.038). I-TAC did not defer significantly with rejection. CXCR3 mRNA
persistently elevated after cardiac transplantation. Double
immunohistochemistry revealed differential cellular distribution of
CXCR3 chemokines. Intragraft vascular cells expressed high levels of
IP-10 and I-TAC, while Mig localized predominantly in infiltrating
macrophages. CXCR3 was localized in vascular and infiltrating cells.
CXCR3 chemokines are induced in cardiac allografts and differentially
associated with CAV and rejection. Differential cellular distribution
of these chemokines in allografts indicates their central roles in
multiple pathways involving CAV and rejection. This chemokine pathway
may serve as a monitor and target for novel therapies to prevent CAV
and rejection.
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