Case 4 -
Sudden Cardiac Death
Richard N. Mitchell
Brigham and Women's Hospital
Click on each slide thumbnail image for an enlarged view
The patient was a 34 year old male with a history of congenital heart disease (D-transposition of the
great arteries); a Mustard repair procedure at age 4 was complicated by right phrenic nerve damage and
right diaphragmatic paralysis. He subsequently developed progressive failure of his systemic ventricle,
and underwent cardiac transplantation in 1990 (at the age of 22); his post-transplant immunosuppression
consisted of cyclosporine A, azothioprine, and corticosteroids. His course was notable for two episodes
of acute rejection in the first year following transplantation, treated with solumedrol boluses. In
addition, within 4 months of transplant, he developed a post-transplant lymphoma in a left submandibular
node. This was resected, and he experienced no further recurrence after his immunosuppressive therapy
was slightly tapered. Other complications included obesity (eventually developing Pickwickian
symptomatology), hypertension, osteoporosis, and hyperlipidemia.
Slide 12 - Anterior half of heart sectioned in an echocardiographic 4-chamber view. The lateral free wall and mid-septal walls exhibit focal scarring, as well as depressed glassy-appearing areas indicating granulation tissue.
Slide 13 - Section from mid-left anterior descending coronary artery demonstrating moderate concentric intimal hyperplasia consisting of chronic inflammatory cells, smooth muscle cells, and extracellular matrix. This is representative of the appearance of all the epicardial arteries as well as many of the penetrating intramyocardial arterioles.
Slide 14 - Section of interventricular septum exhibiting diffuse, severe subendocardial myocyte vacuolization indicative of chronic sub-lethal ischemic injury. When seen on routine endomyocardial biopsy in transplant recipients, these changes are highly specific for allograft arteriopathy (See reference: Winters GL and Schoen FJ. J Heart Lung Transplant 1997;16:985-993).
Slide 15 - Section of left ventricular free wall showing well-circumscribed subendocardial microscopic infarction. Such watershed microscopic infarcts are also strongly associated with allograft arteriopathy (See reference: Winters GL and Schoen FJ. J Heart Lung Transplant 1997;16:985-993).
The patient had annual angiographic evaluation of his coronaries; beginning approximately 10 years
after transplant, diffuse coronary artery disease was first seen, most apparent in the smaller coronary
arteries. Intravascular ultrasound also documented moderate-severe diffuse epicardial vessel disease
with up to 85% chronic stenoses. Beginning 11 years after transplant, the patient developed progressive,
severe exertional dyspnea and biventricular failure (R>L), although ejection fractions were largely
maintained; moderate pulmonary hypertension was documented. PFT's documented profound restrictive and
obstructive lung disease; although he was found to be a carrier for cystic fibrosis, his findings were
felt overall to be most consistent with central neurogenic hypoventilation.
The patient presented terminally with right lower abdomenal discomfort; CT evaluation showed only
mild thickening of the distal ileum and he was discharged to be worked up electively. He subsequently
suffered a cardiac arrest at home, and could not be resuscitated. Slides available for review are a
representative coronary artery and myocardium from the failed allograft.
- allograft arteriopathy with sudden cardiac death
- pulmonary embolism
- GI perforation/hemorrhage due to lymphoma or opportunistic infection
- severe acute rejection
The lungs showed only minimal edema (combined weights of 920 g), and focal non-specific parenchymal
hemorrhage; there was no evidence of acute or remote embolization, and no significant parenchymal
fibrosis. The liver exhibited only mild central congestion. The kidneys were severely autolyzed and
arteriolar hyalinization could not be evaluated. There was no morphologic cause apparent to explain the
pre-terminal right lower quadrant pain; specifically there was no evidence of gastrointestinal tract
ischemia, infarction, or inflammation. There was no mesenteric lymphadenopathy, and no evidence of
lymphoma. Post-mortem cultures showed only typical post-mortem contaminants.
The heart exhibited moderate cardiomegaly (wt = 600 g), with well-healed atrial and vascular
anastomoses. There was biventricular hypertrophy and moderate biventricular dilation, with mild-moderate
myxomatous degeneration of the mitral valve and a bland, poorly organized thrombus on the anterior
leaflet of the mitral valve. Grossly, there was evidence of focal remote myocardial scarring, as well as
focal granulation tissue consistent with more recent infarction. There was moderate diffuse concentric
intimal hyperplasia of all major epicardial vessels (allograft arteriopathy) causing 50-70% chronic
stenoses without any acute thrombosis. Notably, the intramyocardial arterioles exhibited severe
allograft arteriopathy with focal sub-total occlusions (see histology sections). The myocardium
exhibited diffuse subendocardial myocyte vacuolization indicative of chronic low-grade ischemia; focal
remote sub-endocardial microscopic infarcts were also present, consistent with allograft arteriopathy.
In addition, focal scattered acute rejection with myocyte injury and Quilty A-type lesions were also
present, without any significant myocardial edema.
Sudden cardiac death in the setting of remote and recent myocardial
infarctions, secondary to allograft arteriopathy 12 years status post cardiac
Despite excellent therapies to prevent and treat acute allograft rejection, successful long-term
solid organ transplant survival continues to be limited by allograft arteriopathy. With a mean onset of
detectable pathology at approximately 5-7 years, transplanted organs typically develop severe, diffuse
intimal hyperplastic lesions leading eventually to lumenal stenoses and to ischemic graft failure. The
intimal lesions, variously called chronic rejection, allograft arteriopathy, graft vascular sclerosis,
graft arterial disease, or transplant associated arteriosclerosis, result from an initial alloimmune
response, although the entire set of effector mechanisms remain to be elucidated.1, 2 The lesions
consist primarily of smooth muscle cells (SMC) and associated extracellular matrix, admixed with
infiltrating mononuclear leukocytes. Until recently, the working hypothesis was that low-level
endothelial or perivascular immune responses induced persistent allograft vascular damage.1, 3 In
turn, inflammatory cells, and/or activated, dysfunctional endothelial cells (EC) and medial SMC would
secrete growth factors that induced the migration of SMC from the donor media into the arterial intima,
as well as stimulated their proliferation and matrix synthesis. This hypothesis has now been modified by
the recent demonstration in aortic and heart experimental models,4-8 as well as in human renal
transplantation,9 that intimal SMC are actually derived from circulating host precursors.
Allograft arteriopathy (AA)
In the current era of immunosuppression,
graft failure due to acute rejection occurs relatively infrequently, and one-year survival statistics for
most solid organs exceeds 90%. Thus, AA has emerged as the principal barrier to long-term solid organ
allograft survival; interestingly, it is most prevalent in cardiac transplants.10, 11 In the case of
cardiac allografts, patients may develop congestive heart failure due to progressive loss of functioning
myocardium, or they may have a sudden cardiac death due to a lethal arrhythmia or large infarct.12
Distressingly, AA lesions occur even in the setting of immunosuppression regimens adequate to block most
acute parenchymal rejection and does not strictly correlate with episodes or severity of allograft
As an integral part of an allograft, vessels will experience acute rejection prior to the development
of AA. A number of workers have shown that although acute rejection episodes do not strictly correlate
with the development of AA, transient acute rejection may potentiate the process.14-16 Consequently,
AA likely occurs predominantly as a consequence of immune-mediated allospecific vascular injury in grafts,1 most
likely a form of delayed-type hypersensitivity (DTH). The chronicity of the disease may be due
a DTH response which is intrinsically ineffective in eliminate donor antigen (i.e., the EC). There is
evidence that allogeneic EC induce a unique subset of cytolytic CD8+ T cells,17, 18 which are less
efficient at target cell killing. As a source of persistent alloantigen, donor arterial vascular wall EC
and medial SMC are still present in long-term murine cardiac allografts that had already developed
Moreover, AA does not require on-going allogeneic stimulation. Thus, transient acute rejection with
subsequent complete ablation of the alloantigen response,15 or return of an allograft into an
autologous recipient after an episode of rejection20-22 still culminates in AA lesions. The
implication is that initial allospecific activation may cause the recruitment and activation of secondary
effector cells, including macrophages and natural killer (NK) cells. Through specific cellular
recruitment (via chemokines) and subsequent development of a local milieu of inflammatory mediators
(called cytokines), these cells may establish an environment sufficient for the subsequent
alloantigen-independent development of AA. Peri-operative ischemic injury,23 antibody-mediated
processes,24-26 cytokine-induced endothelial dysfunction, and toxic or infectious insults (e.g. with
CMV or other viruses27-29 may also contribute to alloantigen-independent activation of EC, SMC, or
inflammatory cells and may serve to amplify the allospecific pathways.
Role of cytokines in AA
Cytokines are protein mediators that are
secreted by a variety of cell types, and in general have pleiotropic effects. Many cytokines are
produced primarily by cells mediating antigen-specific immunity (e.g., T and B cells) and have roles in
modulating immunologic responses. Some of these act in an autocrine or paracrine fashion,to influence
the behavior of neighboring T and B cells. Other cytokines act primarily on non-lymphoid cells such as
macrophages, SMC, and EC. For example, interferon- g (IFN- g ) activates macrophages, augments
inflammatory cell recruitment by up-regulating adhesion molecules and chemokine expression, and amplifies
immune responses by increasing MHC I and II expression on antigen presenting cells (APC) and.30
Cytokines produced by antigen non-specific cells (e.g., macrophages) generally play a broad role in
stimulating or inhibiting inflammatory responses. In this category are interleukin (IL)-1 and tumor
necrosis factor- a (TNF- a ),both of which have sweeping pro-inflammatory actions including EC activation
(promoting inflammatory cell adhesion and pro-coagulant activity) and SMC proliferation and synthetic
function. Relevant to the pathogenesis of AA, some cytokines (e.g., TGF b )may also induce a local
fibrosing response.31, 32 The observations that EC and SMC can differentially activate T
cells--potentially via specific cytokine and chemokine elaboration-33-35 -suggest a complex set of
interactions occurring in the cytokine milieu of the vessel wall.
IFNg is a cytokine central to the development of AA. Intimal lesions do not occur in heterotopic
cardiac allografts in IFN g -deficient mice despite ongoing parenchymal rejection;15, 36 comparable
results were seen in wild-type (WT) recipients receiving weekly injections of anti-IFN g antibodies.36 Relative to
grafts transplanted into WT recipients, allografts transplanted into IFN g -deficient
hosts showed similar (or even increased) numbers of helper and cytotoxic T cells, as well as
macrophages. Nevertheless, cardiac allografts in IFN g -deficient recipients exhibited diminished
co-stimulator and adhesion molecule expression relative to control recipients.36 IFNg can also
potently affect the development of AA by inducing the vascular production of chemokines (see below) that
regulate mononuclear inflammatory cell recruitment.
Based on these observations, it has been previously proposed that AA results from an initial
alloresponse (and potentially from other forms of vascular injury) leading to secondary recruitment and
activation of macrophages in a process largely driven by IFN g.36 In this model, the antigen
non-specific mononuclear phagocytes subsequently elaborate fibrogenic mediators such as TGF b , as well
as SMC growth stimulators such as IL-1 and TNFa.1 Consequently, proximal blockade of IFN g , or some
of its distal effects (e.g., macrophage recruitment and/or activation) during periods of parenchymal
rejection could conceivably ameliorate the later development of AA. To date, no such IFN g -blocking
therapeutic agent has been identified for treating human disease.
It is also noteworthy that IFN g (frequently in conjunction with TNFa ) has been shown to regulate
the expression of chemokines, chemokine receptors, and adhesion molecules that direct the recruitment and
activation of SMC in atherosclerotic plaque.37-39 Although IFNg inhibits medial SMC proliferation in
vitro,40 the presence or absence of IFN g correlates with the extent of disease in murine models of
atherosclerosis. It is therefore conceivable that intimal SMC in AA may respond differently that medial
SMC to this cytokine (and others in the perivascular cytokine milieu), and that the efficacy of IFN g
blockade may in part derive from diminished SMC recruitment and/or activation.
Role of chemokines in AA
Chemokines are small molecular weight (8-10 kD)
secreted proteins responsible for the recruitment and activation of a variety of inflammatory and
non-inflammatory cells. Greater than 50 chemokines have been identified and are broadly classified into
four sub-families based on the position of internal cysteine residues (e.g., adjacent cysteines in the CC
chemokines, or cysteines separated by some other amino acid in CXC chemokines). For example, mediators
responsible for the recruitment of neutrophils and monocyte-macrophages involved in innate immunity
include the so-called CXC chemokines such as macrophage inflammatory protein-2 a (MIP-2 a ), Gro a , and
interleukin-8, as well as CC chemokines such as macrophage chemoattractant protein-1 (MCP-1). Mediators
that contribute to the recruitment of antigen-specific T cells include CXC chemokines such as monokine
induced by IFNg (Mig), IFN g -inducible protein 10 (IP-10), and IFN g -inducible T cell alpha
chemoattractant (I-TAC), as well as CC chemokines like RANTES (regulated upon activation, normal T cell
expressed and secreted). Of the CXC chemokines, IP-10, Mig, and I-TAC are all strongly expressed by IFNg
; this is again noteworthy since the absence of IFN g abrogates the development of AA, as described above.15, 36 The role
of these molecules in acute allograft rejection has been the subject of a number of
recent excellent reviews,41-44 although potentially unique roles for chemokines in the development of
AA have not been detailed.
Chemokine receptors are G-protein coupled seven transmembrane-spanning proteins with discrete
cellular distributions and binding specificities;34, 45 there are over 20 so far described.
Graft EC represent the initial site where host inflammatory cells encounter and recognize foreign
donor MHC. Recipient inflammatory cells must adhere to EC and subsequently pass through the vessel wall
into the donor parenchyma. The process begins with antigen non-specific neutrophils and
monocyte/macrophages, cells of innate immunity recruited into allografts as a consequence of allograft
ischemic injury.42, 46 This initial wave promotes the recruitment and activation of alloreactive T
cells, which in turn drive the recruitment of additional macrophages, and eventually host-derived SMC
precursors leading to AA. Interrupting chemokine cellular conscription pathways at any of these
stages-innate immunity, allospecific immune responses, secondary macrophage recruitment, or intimal
SMC-can potentially yield beneficial effects in attenuating the development of AA lesions.
The plethora of chemokines and receptors, as well as the apparent promiscuity of chemokine-receptor
interactions, raises the relevant issue whether any single chemokine (e.g., MCP-1) or receptor can have a
central non-redundant role in a given inflammatory process such as AA. It appears that selected MCP-1 or
CCR2 ablations in genetically-deficient mice do materially impact monocyte recruitment and activation in
delayed-type hypersensitivity lesions47, 48 and attenuate the development of atherosclerosis.49,50 Relevant
to transplantation, monoclonal antibody blockade of the IFN g -induced chemokine Mig
diminished allograft rejection.51 Targeted deletion of the CCR1 chemokine receptor reduced both acute
parenchymal rejection, as well as the development of AA.52 Moreover, a selective non-peptide CCR1
receptor antagonist (BX471) developed by Berlex Biosciences (Richmond, CA) has efficacy in acute cardiac
rejection models in rats and rabbits.53, 54
Source of intimal cells in AA
A subpopulation of peripheral circulating
cells and bone marrow cells can differentiate into EC.55, 56 However, the majority of EC (as well as
the medial SMC) lining AA lesions in long-term cardiac allografts are donor-derived.4, 19, 57 The
observation concerning the identity of arteriolar EC in cardiac allografts is significant in that
persistence of donor cells may well continue to drive an alloresponse that culminates in AA lesions.
In some experimental models, host EC can seed synthetic vascular grafts implanted in vivo,58 and
host SMC are identified in synthetic grafts and some arterial allograft models.58, 59 Despite these
findings, it was generally assumed that the majority of intimal SMC in AA lesions originated by ingrowth
of donor SMC from the media of engrafted vessels.60 These assumptions led to unsuccessful
experimental molecular interventions (e.g., gene therapy) targeting donor medial SMC proliferation to
ameliorate AA.61, 62
It was subsequently shown that intimal SMC in vascular grafts are virtually all host-derived;4-6,8 in
particular, it has been demonstrated that a proportion of these could originate from host bone
marrow-derived cells.8 This result is consistent with the recent finding that bone marrow stem cells
are capable of developing into multiple mesenchymal lineages.63 It also suggests that intimal SMC may
have a functional phenotype distinct from the underlying vascular wall medial SMC, and may also have
unique chemokine and cytokine responsiveness.
- Libby, P., et al., Functions of vascular wall cells related to the development of
transplant-associated coronary arteriosclerosis. Transplant. Proc.,1989. 21: p. 3677-3684.
- Libby, P. and J. Pober, Chronic rejection. Immunity, 2001. 14: p. 387-397.
- Libby, P. and H. Tanaka, The pathogenesis of coronary arteriosclerosis ("chronic
rejection") in transplanted hearts. Clin. Transplant., 1994. 8: p. 327-332.
- Hillebrands, J., et al., Origin of neointimal endothelium and alpha-actin-positive smooth muscle
cells in transplant arteriosclerosis. J. Clin. Invest., 2001. 107: p. 1411-1422.
- Li, J., et al., Vascular smooth muscle cells of recipient origin mediate intimal expansion after
aortic allotransplantation in mice. Am. J. Pathol., 2001. 158: p. 1943-1947.
- Saiura, A., et al., Circulating smooth muscle progenitor cells contribute to atherosclerosis. Nature
Med., 2001. 7: p. 382-383.
- Shimizu, K., et al., Host bone-marrow cells are a source of donor intimal smooth muscle-like cells in
murine aortic transplant arteriopathy. Circ., 2000. 102: p. II-221, II-V.
- Shimizu, K., et al., Host bone-marrow cells are a source of donor intimal smooth muscle-like cells in
murine aortic transplant arteriopathy. Nature Med., 2001. 7: p. 738-741.
- Grimm, P., et al., Neointimal and tubulointerstitial infiltration by recipient mesencymal cells in
chronic renal-allograft rejection. N. Eng. J. Med., 2001. 345: p. 93-97.
- Costanzo, M., et al., Heart transplant coronary artery disease detected by coronary angiography: A
multi-institutional study of preoperative donor and recipient risk factors. J. Heart Lung Transplant.,
1998. 17: p. 744-753.
- Hosenpud, J., et al., The Registry of the International Society for Heart and lung transplantation:
Fifteenth official report-1998. J. Heart Lung Transplant., 1998. 17: p. 656-668.
- Schoen, F. and P. Libby, Cardiac transplant graft arteriosclerosis. Trends Cardiovasc. Med., 1991.
1: p. 216-223.
- Hauptman, P., et al., Acute rejection: Culprit or coincidence in the pathogenesis of cardiac graft
vascular disease? J. Heart Lung Transplant., 1995. 14: p. S173-S180.
- Geerling, R., et al., Suppression of acute rejection prevents graft arteriosclerosis after allogeneic
aorta transplantation in the rat. Transplant., 1994. 58: p. 1258-1263.
- Nagano, H., et al., Coronary arteriosclerosis after T-cell-mediated injury in transplanted mouse
hearts. Role of Interferon-g. Am. J. Pathol., 1998. 152: p. 1187-1197.
- Nakagawa, T., et al., Acute rejection accelerates graft coronary disease in transplanted rabbit
hearts. Circ., 1995. 92: p. 987-993.
- Biedermann, B. and J. Pober, Human endothelial cells induce and regulate cytolytic T cell
differentiation. J. Immunol., 1998. 161: p. 4679-4687.
- Biedermann, B. and J. Pober, Human vascular endothelial cells favor clonal expansion of unusual
alloreactive CTL. J. Immunol., 1999. 162: p. 7022-7030.
- Hasegawa, S., et al., Pattern of graft- and host-specific MHC class II expression in long-term murine
cardiac allografts. Origin of inflammatory and vascular wall cells. Am. J. Pathol., 1998. 153: p.
- Hullett, D., et al., The impact of acute rejection on the development of intimal hyperplasia
associated with chronic rejection. Transplant., 1996. 62: p. 1842-1846.
- Izutani, H., et al., Evidence that graft coronary arteriosclerosis begins in the early phase after
transplantation and progresses without chronic immunoreaction. Transplant., 1995. 60: p. 1073-1079.
- Tullius, S., et al., Reversibility of chronic renal allograft rejection: Critical effect of time
after transplantation suggests both host immune-dependent and -independent phases of progressive injury.
Transplant., 1994. 58: p. 93-99.
- Tilney, N. and R. Guttmann, Effects of initial ischemia/reperfusion injury on the transplanted
kidney. Transplant., 1997. 64: p.945-947.
- Hancock, W., et al., Antibody-induced transplant arteriosclerosis is prevented by graft expression of
anti-oxidant and anti-apoptotic genes. Nature Med., 1998. 4: p. 1392-1396.
- Russell, P., et al., Coronary atherosclerosis in transplanted mouse hearts. II. Importance of
humoral immunity. J. Immunol., 1994. 152: p. 5135-5141.
- Shi, C., et al., Immunologic basis of transplant associated arteriosclerosis. Proc. Natl. Acad.
Sci. (USA), 1996. 93: p. 4051-4056.
- Everett, J., et al., Prolonged cytomegalovirus infection with viremia is associated with development
of cardiac allograft vasculopathy. J. Heart Lung Transplant., 1992. 11: p. S133-S137.
- Loebe, M., et al., Role of cytomegalovirus infection in the development of coronary artery disease in
the transplanted heart. J. Heart Lung Transplant., 1990. 9: p. 707-711.
- Nagano, H., et al., Infection-associated macrophage activation accelerates chronic renal allograft
rejection in rats. Transplant., 1997. 64: p. 1602-1605.
- Farrar, M. and R. Schreiber, The molecular cell biology of interferon-gamma and its receptor. Ann.
Rev. Immunol., 1993. 11: p. 571-611.
- Postlethwaite, A., Role of T cells and cytokines in effecting fibrosis. Int. Rev. Immunol., 1995.
12: p. 247-258.
- Roberts, A. and M. Sporn, Physiologic actions and clinical applications of transforming growth
factor-beta (TGF-beta). Growth Factors, 1993. 8: p. 1-9.
- Fabry, Z., et al., Antigen presentation by brain microvessel smooth muscle and endothelium. J.
Neuroimmunol., 1990. 28: p. 63-71.
- Rossi, D. and A. Zlotnick, The biology of chemokines and their receptors. Ann. Rev. Immunol.,
2000. 18: p. 217-242.
- Ward, S., K. Bacon, and J. Westwick, Chemokines and T lymphocytes: More than an attraction.
Immunity, 1998. 9: p. 1-11.
- Nagano, H., et al., Interferon-g deficiency prevents coronary arteriosclerosis but not myocardial
rejection in transplanted mouse hearts. J. Clin. Invest., 1997. 100: p. 550-557.
- Hansson, G., Immune mechanisms in atherosclerosis. Arterioscler. Thromb. Vasc. Biol., 2001. 21:
- Laurat, E., et al., In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis
in apolipoprotein E-knockout mice. Circ., 2001. 104: p. 197-202.
- Plutzky, J., Inflammatory pathways in atherosclerosis and acute coronary syndromes. Am. J.
Cardiol., 2001. 88: p. 10K-15K.
- Hansson, G., et al., Gamma interferon regulates vascular smooth muscle proliferation and Ia
expression in vivo and in vitro. Circ. Res., 1988. 63: p. 712-719.
- Colvin, B. and A. Thomson, Chemokines, their receptors and transplant outcome. Transplantation,
2002. 74: p. 149-155.
- El-Sawy, T., N. Fahmy, and R. Fairchild, Chemokines: Directing leukocyte traffic into allografts.
Curr. Opin. Immunol., 2002. 14: p. 562-568.
- Nelson, P. and A. Krensky, Chemokines, chemokine receptors, and allograft rejection. Immunity, 2001.
14: p. 377-386.
- Nelson, P. and A. Krensky, Chemokines and allograft rejection: Narrowing the list of suspects.
Transplantation, 2001. 72: p. 1195-1197.
- Luster, A., Chemokines: Chemotactic cytokines that mediate inflammation. N. Eng. J. Med., 1998.
338: p. 436-445.
- Morita, K., et al., Early chemokine cascades in murine cardiac grafts regulate T cell recruitment and
progression of acute allograft rejection. J. Immunol., 2001. 167: p. 2979-2984.
- Boring, L., et al., Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in CCR2
knockout mice. J. Clin. Invest., 1997. 100: p. 2552-2561.
- Gu, L., et al., In vivo properties of monocyte chemoattractant protein-1. J. Leukoc. Biol., 1997.
62: p. 577-580.
- Aiello, R., et al., Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein
E-deficient mice. Aretriosler. Thromb. Vasc. Biol., 1999. 19: p. 1518-1525.
- Gosling, J., et al., MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that
overexpress human apolipoprotein B. J. Clin. Invest., 1999. 103: p. 773-778.
- Koga, S., et al., T cell infiltration into class II MHC-disparate allografts and acute rejection is
dependent on the IFN-gamma-induced chemokine Mig. J. Immunol., 1999. 163: p. 4878- 4885.
- Gao, W., et al., Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic
cardiac allograft rejection. J. Clin. Invest., 2000. 105: p. 35-44.
- Horuk, R., et al., CCR1-specific non-peptide antagonist: Efficacy in a rabbit allograft rejection
model. Immunol. Lett., 2001. 76: p. CCR1-specific non-peptide antagonist: efficacy in a rabbit
allograft rejection model.
- Horuk, R., et al., A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in
rat heart transplant rejection. J. Biol. Chem., 2001. 276: p. 4199-4204.
- Asahara, T., et al., Isolation of putative progenitor endothelial cells for angiogenesis. Science,
1997. 275: p. 964-967.
- Lin, Y., et al., Origins of circulating endothelial cells and endothelial outgrowth from blood. J.
Clin. Invest., 2000. 105: p. 71-77.
- Hillebrands, J., et al., Bone marrow does not contribute substantially to endothelial-cell
replacement in transplant arteriosclerosis. Nat. Med., 2002. 8: p. 194-195.
- Campbell, J., J. Efendy, and G. Campbell, Novel vascular graft grown within recipient's own
peritoneal cavity. Circ. Res., 1999. 85: p. 1173-1178.
- Plissonier, D., et al., Sequential immunological targeting of chronic experimental arterial
allograft. Transplant., 1995. 60: p. 414-424.
- Kennedy, L. and I. Weissman, Dual origin of intimal cells in cardiac-allograft arteriosclerosis. N.
Engl. J. Med., 1971. 285: p. 884-887.
- Gibbons, G. and V. Dzau, Molecular therapies for vascular diseases. Science, 1996. 272: p. 689-693.
- Mann, M., et al., Genetic engineering of vein grafts resistant to atherosclerosis. Proc. Natl.
Acad. Sci. USA, 1995. 92: p. 4502-4506.
- Pittenger, M., et al., Multilineage potential of adult human mesenchymal stem cells. Science, 1999.
284: p. 143-147.