Name: mouse model of alloimmune-induced vascular rejection and transplant arteriosclerosis
Uploaded: 2015-05-17T14:00:00
Description: Watch this Scientific Journal Video about Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis at JoVE.com

This work was supported by grants from the Canadian Institutes of Health Research and Heart and Stroke Foundation of BC &#38; Yukon (JCC).

All the protocols in this study were reviewed and approved by the Simon Fraser University animal care ethics committee. Use Balb/cYJ (H2d) donor mice and C57Bl/6 (H2b) recipient mice to examine allogeneic reactions. Mice are used for experiments between the ages of 8 to 12 weeks. Use either female or male mice. Syngeneic controls consist of aortic segments from C57Bl/6 donors into C57Bl/6 recipients.
1. Donor and Recipient Preparation
Note: Both the donor and recipie...

<ol>
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C., Kerjner, A., Wong, B. W., McManus, B. M., Granville, D. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Perforin+mediates+endothelial+cell+death+and+resultant+transplant+vascular+disease+in+cardiac+allografts.">Perforin mediates endothelial cell death and resultant transplant vascular disease in cardiac allografts.</a> Am J Pathol. 165, 127-133 (2004).</li><li>Choy, J. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Granzyme+B+induces+endothelial+cell+apoptosis+and+contributes+to+the+development+of+transplant+vascular+disease.">Granzyme B induces endothelial cell apoptosis and contributes to the development of transplant vascular disease.</a> Am J Transplant. 5, 494-499 (2005).</li><li>Reis, E. 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We have described a protocol for aortic interposition grafting in mice that is useful for studying immune-mediated vascular rejection and TA. This model can be used to investigate the causes of TA as well as the development of novel therapeutic strategies. It has been used in the past to establish an essential role of adaptive immunity, cytotoxic T cell responses, cytokine-mediated CD4 T cell effector responses, and antibody-mediated graft damage in TA 14,17-21. Artery transplantation in mice is difficult due ...

Over the past 30+ years, advances in immunosuppressive drugs have diminished graft rejection due to acute rejection but chronic rejection remains a main challenge. The main manifestation of chronic heart transplant rejection is transplant arteriosclerosis (TA) 1,2. This condition is characterized by intimal hyperplasia and vasomotor dysfunction of allograft arteries and develops as a result of immunological targeting of endothelial and smooth muscle cells by the recipient immune system. The specific targeting of the graft vasculature due to recognition of foreign peptide-major histocompatibility complex (MHC) is highlighted by the development of TA exclusively in graft arteries while sparing host vessels 3. In keeping with this is the observation that TA does not occur experimentally when the recipient is genetically identical to the donor or when the recipient lacks T and B cells 4. Immune-mediated vascular injury and dysfunction causes the development of intimal thickening and fibrosis, as well as the aberrant accumulation of lipids and ECM proteins, in TA 5. Intimal thickening tends to be concentric throughout the entire arterial tree 4-6. Graft loss and death usually occur as a result of progressive ischemia resulting from luminal occlusion of allograft arteries 4.
In 1991, Mennander et al. 7 pioneered an aortic interposition model in rats to model TA. Several groups have subsequently adapted this procedure for use in mice. In this model, allograft aortic segments develop lesions that have features comparable to TA observed in clinical transplants. This includes intimal thickening characterized by the accumulation of smooth muscle-like cells and recipient leukocytes 7. Over the past 2 decades this model has been used to generate important insight into the mechanisms of vascular injury, rejection and TA. It can be used to examine questions related to immune and vascular responses during arterial pathology. The choice of antigen mismatch impacts the ability to appropriately address these questions.
Transplantation across complete MHC barriers permits a comprehensive evaluation of immune responses that are known to be involved in organ transplant rejection. This includes direct CD4 and CD8 T cell recognition and targeting of foreign peptide-MHC presented by graft-derived cells, indirect CD4 (and possibly CD8) T cell recognition and targeting of graft-derived alloantigens presented by recipient antigen presenting cells, and antibody-mediated recognition of alloantigens on vascular cell surfaces 8. However, the vascular response to injury in complete MHC-mismatched experiments may be different than that observed clinically. Johnson et al. 9 showed that, in aortic interposition grafts transplanted across a complete MHC mismatch barrier, most of the neointimal cells are of recipient origin and not of donor origin. This is different than that observed in human transplants where most intimal smooth muscle cells are of donor origin 9,10. To account for this limitation, alternate experimental models that involve grafting across minor histocompatibility antigen mismatches have been developed that trigger vascular responses that more closely resemble those observed in clinical transplantation 11. While these alternate models allow for important conclusions to be made regarding the vascular responses that drive the development of TA, the immunological processes that cause vascular rejection in minor histocompatibility antigen mismatched grafts do not completely re-capitulate those which occur in the clinical setting. For instance, minor histocompatibility antigens are recognized poorly by graft reactive antibodies 12. Given the above considerations, it is important to consider the pathological question being examined when choosing the type of antigen mismatch used in an aortic interposition model. Here we describe a detailed protocol for murine aortic interposition grafting. We describe interposition grafting between complete MHC-mismatched mice but the same protocol is used for grafting across other antigen mismatched mouse strains.

<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td>Name&#160;</td>
			<td>Company</td>
			<td>Catalogue</td>
			<td>Comments</td>
		</tr>
		<tr>
			<td>C57BL/6J (H-2b)</td>
			<td>Jackson Laboratories, Bar Harbour ME</td>
			<td>Strain# 000664</td>
			<td></td>
		</tr>
		<tr>
			<td>Balb/cBYJ</td>
			<td>Jackson Laboratories, Bar Harbour ME</td>
			<td>Strain# 001026</td>
			<td></td>
		</tr>
		<tr>
			<td rowspan="2">Ketamine Hydrochloride Injection USP 100 mg/ mL</td>
			<td rowspan="2">Ketalean</td>
			<td rowspan="2">DIN 00612316</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
		</tr>
		<tr>
			<td>Xylazine Injection 20 mg/mL</td>
			<td>Rompum</td>
			<td>DIN 02169592</td>
			<td></td>
		</tr>
		<tr>
			<td>Ketoprofen Injection 100 mg/mL</td>
			<td>Anafen</td>
			<td>DIN 01938126</td>
			<td></td>
		</tr>
		<tr>
			<td>Butorphanol Tartrate&#160;injection 10 mg/mL</td>
			<td>Torbugesic</td>
			<td>DIN 008450000</td>
			<td></td>
		</tr>
		<tr>
			<td>Buprenorphine Injection 0.3 mg/mL</td>
			<td>Reckitt Benckiser</td>
			<td>B.N. 5241</td>
			<td></td>
		</tr>
		<tr>
			<td>Atipamezole hydrochloride sterile injectable solution</td>
			<td>Antisedan</td>
			<td>DIN 02237744</td>
			<td></td>
		</tr>
		<tr>
			<td>Heparin Sodium Injection, USP, 1000 units/mL</td>
			<td>McKesson Distribution</td>
			<td>DIN 02264315</td>
			<td></td>
		</tr>
		<tr>
			<td>Tears naturale ophthalmic ointment</td>
			<td>Alcon</td>
			<td>DIN 02082519</td>
			<td></td>
		</tr>
		<tr>
			<td>Stereomicroscope</td>
			<td>Leica</td>
			<td>M80</td>
			<td></td>
		</tr>
		<tr>
			<td>0.9% Sodium Chloride, sterile</td>
			<td>Baxter Corporation</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Lactated Ringer&#8217;s solution, sterile</td>
			<td>Baxter Corporation</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>0.9% Sodium Chloride Injection, sterile, 10 mL</td>
			<td>Baxter Corporation</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Alcohol Prep Pads</td>
			<td>Loris</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Povidone Iodine</td>
			<td>Betadine</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Chlorohexidine Gluconate 4% w/v</td>
			<td>Germi-Stat</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Black Polyamide Monofilament</td>
			<td>AROSurgical Instruments</td>
			<td rowspan="2">T4A10Q07</td>
			<td></td>
		</tr>
		<tr>
			<td>Suture, 10-0 suture, 70 microns</td>
			<td>Corporation</td>
			<td></td>
		</tr>
		<tr>
			<td>Blue monofilament suture 5-0, P3 needle</td>
			<td>Ethicon</td>
			<td>8698G</td>
			<td></td>
		</tr>
		<tr>
			<td>1 ml Syringe</td>
			<td>BD</td>
			<td>REF 309659</td>
			<td></td>
		</tr>
		<tr>
			<td>10 ml Syringe</td>
			<td>BD</td>
			<td>REF 309604</td>
			<td></td>
		</tr>
		<tr>
			<td>1cc TB insulin syringe with 28G 1/2</td>
			<td>BD</td>
			<td>REF 309309</td>
			<td></td>
		</tr>
		<tr>
			<td>25G 7/8, hypodermic needle</td>
			<td>BD</td>
			<td>REF 305124</td>
			<td></td>
		</tr>
		<tr>
			<td>27G 1/2, hypodermic needle</td>
			<td>BD</td>
			<td>REF 305109</td>
			<td></td>
		</tr>
		<tr>
			<td>Colibri Retractor- 1.5cm spread 4cm</td>
			<td>Fine Science Tools</td>
			<td>17000-04</td>
			<td></td>
		</tr>
		<tr>
			<td>S&#38;T CAF-4 Clip applying forceps, without lock</td>
			<td>Fine Science Tools</td>
			<td>00072-14</td>
			<td></td>
		</tr>
		<tr>
			<td>Supergrip forceps, S&#38;T</td>
			<td>Fine Science Tools</td>
			<td>00632-11</td>
			<td></td>
		</tr>
		<tr>
			<td>Medical No.5 forceps</td>
			<td>Fine Science Tools</td>
			<td>11253-20</td>
			<td></td>
		</tr>
		<tr>
			<td>Lexer Baby Scissors</td>
			<td>Fine Science Tools</td>
			<td>14078-10</td>
			<td></td>
		</tr>
		<tr>
			<td>Micro Adson forceps serrated</td>
			<td>Fine Science Tools</td>
			<td>11018-12</td>
			<td></td>
		</tr>
		<tr>
			<td>Vannas-Tubingen microscissors</td>
			<td>Fine Science Tools</td>
			<td>15003-08</td>
			<td></td>
		</tr>
		<tr>
			<td>Micro clamps, b-1; 3.5mm x 1mm; 7mm length</td>
			<td>Fine Science Tools</td>
			<td>00396-01</td>
			<td></td>
		</tr>
		<tr>
			<td>Graefe-forceps, 10cm 1x2 teeth</td>
			<td>Fine Science Tools</td>
			<td>11054-10</td>
			<td></td>
		</tr>
		<tr>
			<td>Castroviejo with lock and tungsten jaws</td>
			<td>Fine Science Tools</td>
			<td>12565-14</td>
			<td></td>
		</tr>
		<tr>
			<td>Hot glass bead sterilizer</td>
			<td>Inotech 250</td>
			<td>IS-250 - Steri-250</td>
			<td></td>
		</tr>
		<tr>
			<td>Non-woven gauzes</td>
			<td>Progene</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Cotton Tipped Applicators</td>
			<td>Puritan</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Beard Trimmer</td>
			<td>Wahl</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Heating pad</td>
			<td>Sunbeam</td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

mouse model of alloimmune-induced vascular rejection and transplant arteriosclerosis

Vascular rejection that leads to transplant arteriosclerosis (TA) is the leading representation of chronic heart transplant failure. In TA, the immune system of the recipient causes damage of the arterial wall and dysfunction of endothelial cells and smooth muscle cells. This triggers a pathological repair response that is characterized by intimal thickening and luminal occlusion. Understanding the mechanisms by which the immune system causes vasculature rejection and TA may inform the development of novel ways to manage graft failure. Here, we describe a mouse aortic interposition model that can be used to study the pathogenic mechanisms of vascular rejection and TA. The model involves grafting of an aortic segment from a donor animal into an allogeneic recipient. Rejection of the artery segment involves alloimmune reactions and results in arterial changes that resemble vascular rejection. The basic technical approach we describe can be used with different mouse strains and targeted interventions to answer specific questions related to vascular rejection and TA.

In this model, the abdominal aorta from a Balb/cYJ mouse is interposed into the infrarenal aorta of a C57Bl/6 recipient. This permits a comprehensive evaluation of alloimmune responses that target allograft arteries. Immune-mediated vascular injury in this model initiates vascular reparative responses that culminate in intimal thickening, luminal narrowing and recruitment of immune cells (Figures 1 and 2). These criteria then serve as a read-out for the severity of alloimmune responses, ...

Watch this Scientific Journal Video about Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis at JoVE.com

Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis

We describe a protocol for aortic interposition grafting in mice. The goal of the protocol is to provide a model with which to study pathological processes and therapeutic strategies relevant to alloimmune reactions in arteries and the resultant arterial changes that contribute to organ transplant failure.

Vascular rejection that leads to transplant arteriosclerosis (TA) is the leading representation of chronic heart transplant failure. In TA, the immune ...

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Technical aspects of creating an arteriovenous fistula in the mouse are discussed. Under general anesthesia, an abdominal incision is made, and the aorta ...

Murine Heterotopic Heart Transplant Technique

It is now over forty years since this technique was first reported by Corry, Wynn and Russell. Although it took some years for other labs to become ...

Mouse Kidney Transplantation: Models of Allograft Rejection

Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely ...

Ferric Chloride-induced Thrombosis Mouse Model on Carotid Artery and Mesentery Vessel

Severe thrombosis and its ischemic consequences such as myocardial infarction, pulmonary embolism and stroke are major worldwide health issues. The ferric ...

Intraluminal Drug Delivery to the Mouse Arteriovenous Fistula Endothelium

Delivery of therapeutic agents to enhance arteriovenous fistula (AVF) maturation can be administered either via intraluminal or external routes. The ...

Using the Sleeve Technique in a Mouse Model of Aortic Transplantation - An Instructional Video

Orthotopic aortic transplantation using the sleeve technique reduces injury to the aorta with failure rate of only 10-20%. The time to anastomose the ...

Balloon-based Injury to Induce Myointimal Hyperplasia in the Mouse Abdominal Aorta

The use of animal models is essential for a better understanding of MH, one major cause for arterial stenosis.In this article, we demonstrate a murine ...

Quantitative Micro-CT Analysis of Aortopathy in a Mouse Model of &#946;-aminopropionitrile-induced Aortic Aneurysm and Dissection

Aortic aneurysm and dissection is associated with significant morbidity and mortality in the population and can be highly lethal. While animal models of ...