Although most published studies involving preclinical mouse models of cardiac allograft
rejection tend to center on the issues of acute rejection and tolerance induction,
arguably the more pressing need in the field of clinical transplantation is better
understanding of chronic allograft injury. That is, chronic graft injury is a far
greater current clinical problem than is early graft loss due to acute rejection.
In heart transplantation, cardiac allograft vasculopathy (CAV) is a form of pronounced
coronary artery disease that occurs over time after transplant
1
and remains the major source of transplant loss and recipient mortality.
2
,3
Moreover, it has become increasingly apparent over the past several years that the
development of donor-specific antibodies (DSAs) is strongly associated with CAV and
chronic allograft rejection in general through the process of antibody-mediated rejection
(AMR).
4
,5
More importantly, once DSA is generated and CAV occurs, limited treatment options
are available for preventing eventual allograft failure. As such, in addition to advancing
the study of clinical acute and chronic allograft rejection, it is imperative to develop
preclinical animal models that permit greater mechanistic insights into the pathogenesis
of CAV. Identifying suitable mouse models of CAV, especially involving AMR, has been
challenging because useful mouse models need to avoid primary acute rejection and
yet be permissive for generating longer-term chronic allograft injury. Early mouse
models used to generate CAV employed limited antigen disparity between donor and recipient,
such as responses to the minor male H-Y antigen in female recipients
- Berry G.J.
- Burke M.M.
- Andersen C.
- Bruneval P.
- Fedrigo M.
- Fishbein M.C.
- Goddard M.
- Hammond E.H.
- Leone O.
- Marboe C.
- Miller D.
- Neil D.
- Rassl D.
- Revelo M.P.
- Rice A.
- Rene Rodriguez E.
- Stewart S.
- Tan C.D.
- Winters G.L.
- West L.
- Mehra M.R.
- Angelini A.
The 2013 International Society for Heart and Lung Transplantation Working Formulation
for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated
rejection in heart transplantation.
J Heart Lung Transplant. 2013; 32: 1147-1162
6
or to donors that differ from the host at a single major histocompatibility complex
class II molecule.
7
,
8
,
9
However, these models tended to largely invoke a cellular form of chronic rejection
rather than clearly reflect DSA-associated CAV. Another means of developing CAV in
mice is through the treatment of recipients with transient or suboptimal immune-modifying
agents, which results in chronic rather than acute rejection, although the role of
DSA in these models is less defined.
9
,
10
,
11
A more recent approach to assess the role of DSA in triggering CAV is through the
direct transfer of antibodies specific for donor major histocompatibility complex
class I to immune-deficient recipients bearing a cardiac allograft.
12
,13
While these varied approaches have proven useful for studying some aspects of CAV
in mice, there remains an onging need to develop improved animal models of DSA-associated
CAV.To read this article in full you will need to make a payment
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Article Info
Publication History
Published online: May 13, 2022
Accepted:
May 9,
2022
Footnotes
See related article on page 1053
Supported in part by NIH grant R01 DK115745.
Disclosures: None declared.
Identification
Copyright
© 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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- Molecular Signature of Antibody-Mediated Chronic Vasculopathy in Heart Allografts in a Novel Mouse ModelThe American Journal of PathologyVol. 192Issue 7
- PreviewCardiac allograft vasculopathy (CAV) limits the long-term success of heart transplants. Generation of donor-specific antibodies (DSAs) is associated with increased incidence of CAV clinically, but mechanisms underlying development of this pathology remain poorly understood. Major histocompatibility complex–mismatched A/J cardiac allografts in B6.CCR5−/− recipients have been reported to undergo acute rejection with little T-cell infiltration, but intense deposition of C4d in large vessels and capillaries of the graft accompanied by high titers of DSA.
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