وأيد هذا العمل من المنح المقدمة من المعاهد الكندية لأبحاث الصحة والقلب والسكتة الدماغية مؤسسة من قبل الميلاد ويوكون (JCC).

<ol>
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وصفناها بروتوكول للمداخلة الأبهر تطعيم في الفئران يمكن أن يكون مفيدا لدراسة بوساطة المناعي الرفض الأوعية الدموية وTA. هذا النموذج يمكن أن تستخدم للتحقيق في أسباب TA فضلا عن وضع استراتيجيات علاجية جديدة. وقد استخدم في الماضي لإنشاء الدور الأساسي للحصانة التكيفية، السامة للخلايا استجابات الخلايا T، ردود المستجيب CD4 T الخلية بوساطة خلوى، والأجسام المضادة التي تتوسط الضرر الكسب غير المشروع في TA 14،17-21. زرع شريان في الفئران صعب نظرا لصغر حجم واضح للحيوان؛ ومع ذلك، مع الممارسة والعناية الواجبة، ويمكن تحقيق عملية جراحية ناجحة. النجاح يعتمد على المباح للسفينة. هذا ينطوي على ضمان أن الكسب غير المشروع لا تتضرر من جراء التعامل مع غير صحيح السفينة مع ملقط، انقباض في التجويف السفينة، خياطة الجدار الخلفي للسفينة، وخياطة المتكررة من نفس الموقع. تسرب من السفينة هو أيضا مشكلة ويتطلب الحرص على البريدتكفل للتنقسم عدد وموقف غرز بالتساوي في جميع أنحاء جدار الوعاء الدموي. ومن الضروري أيضا أن الكسب غير المشروع نقص التروية يتم التقليل إلى أقل من 30 دقيقة. مع هذا، نسبة نجاح أكبر من 95٪ لا يمكن أن يتحقق. الأبهر هو أكبر شريان في الماوس ولذلك فإن هذا الإجراء هو النهج أبسط المجهرية للتحقيق في رفض الأوعية الدموية في هذا النموذج الحيواني. أيضا، يتم المطعمة قطاع الأبهر في موقع ذات الصلة من الناحية الفسيولوجية، يواجه تدفق الدم الطبيعي، وباطنة سماكة يتطور بسرعة. نموذج الرئيسي الأخرى المستخدمة لتقييم الرفض الأوعية الدموية وTA هو زرع قلب منتبذ، والتي لديها ميزة من دراسة تطوير TA في الشرايين التاجية، وفي سياق زرع القلب وهذا هو السيناريو السريري الأكثر ملاءمة لTA. ومع ذلك، يتم وضعها زرع القلب غيري الموضع في موقع غير الفسيولوجية داخل الجسم (عادة anastamosed إلى الوريد الأجوف والشريان الأبهر في البطن)، والقلب لا يضخ الدم من خلال البطينين نظرا لطبيعة رجعية من إمدادات الدم إلى القلب المزروع. على هذا النحو، وطبيعة تدفق الدم عبر شجرة الشرايين التاجية قد تكون مختلفة عن ما هو من ذوي الخبرة عادة عن طريق الأوعية الدموية التاجية 22،23. أيضا، استراتيجيات للتغلب يجب أن تدمج الرفض الحاد للقلب من أجل تقييم التغيرات في الشرايين. في كلا النموذجين، من المهم أن تختار بعناية نوع المستضد عدم تطابق استخدامها من أجل أن تكون قادرة على التصدي بشكل مناسب أسئلة محددة تتعلق رفض الأوعية الدموية وTA. باختصار، الأبهر مداخلة التطعيم هو أسلوب فعال للتحقيق بوساطة المناعة تضرر الشرايين وTA. ويمكن أن يتقن بشكل روتيني مع الممارسة والاجتهاد من جانب الباحث. مرة واحدة يتقن، يمكن تعديل هذا الإجراء لتطعيم مداخلة قطاعات الشرايين الأخرى، مثل الشريان السباتي، القد تمكن في بحث مسائل علمية إضافية. أيضا، فإن استخدام هذا النموذج يمكن أن تمتد إلى ما بعد دراسة الزرع. مداخلة ترقيع الشرايين يمكن أن تستخدم لإدخال شرائح من الشرايين المعدلة (على سبيل المثال المعدلة وراثيا أو تغذية الدهن) الفئران إلى نظرائهم من غير تعديل، أو العكس بالعكس، لعزل التأثيرات البيولوجية للجزيئات إلى خلايا جدار الشريان مقابل خلايا جدار غير الشريانية 24 25.

على مدى السنوات الماضية 30+، قد تضاءلت التقدم في الأدوية المثبطة للمناعة رفض الكسب غير المشروع بسبب الرفض الحاد ولكن يبقى الرفض المزمن تحديا رئيسيا. مظهر من مظاهر الرئيسي لرفض زرع قلب المزمن هو تصلب الشرايين زرع (TA) 1،2. يتميز هذا الشرط من قبل تضخم باطنة وضعف حركي الشرايين المزروع ويتطور نتيجة لاستهداف المناعية لخلايا العضلات البطانية وسلس من قبل النظام المناعي المتلقي. وسلط الضوء على استهداف معين من الأوعية الدموية الكسب غير المشروع نظرا لاعتراف الأجانب معقد التوافق النسيجي الببتيد الرئيسي (MHC) من خلال تطوير TA حصريا في الشرايين الكسب غير المشروع في حين أن يجنب السفن المضيفة 3. وتمشيا مع هذه هي الملاحظة التي TA لا يحدث تجريبيا عند المتلقي هو متطابقة وراثيا إلى الجهة المانحة أو عند المتلقي يفتقر T و B الخلايا 4. إصابة الأوعية الدموية المناعية وdysfunctioن يتسبب في تطوير سماكة باطنة والتليف، فضلا عن تراكم الدهون الشاذة والبروتينات ECM، في TA 5. باطنة سماكة تميل إلى أن تكون متحدة في جميع أنحاء كامل 4-6 شجرة الشرايين. فقدان الكسب غير المشروع وفاة تحدث عادة نتيجة لنقص التروية التدريجي الناجم عن انسداد الشرايين اللمعية المزروع 4. في عام 1991، Mennander وآخرون. 7 رائدة نموذجا مداخلة الأبهر في الفئران لنموذج TA. لقد عدة مجموعات تكييفها في وقت لاحق هذا الإجراء لاستخدامها في الفئران. في هذا النموذج، وقطاعات الأبهر المزروع تتطور الآفات التي تحتوي على مزايا مماثلة لTA لاحظت في زرع السريرية. وهذا يشمل باطنة سماكة تتميز تراكم خلايا تشبه العضلات الملساء والكريات البيض المتلقي 7. على مدى العقود الماضية 2 وقد استخدم هذا النموذج لتوليد فكرة مهمة في آليات الأوعية الدموية إصابة والرفض وTA. يمكن أن يكون لناإد لبحث المسائل المتعلقة الاستجابات المناعية والأوعية الدموية خلال علم الأمراض في الشرايين. اختيار الآثار مستضد عدم تطابق القدرة على المعالجة الملائمة لهذه الأسئلة. زرع عبر الحواجز MHC كاملة يسمح بإجراء تقييم شامل من الاستجابات المناعية التي تعرف أن تشارك في رفض زرع الأعضاء. وهذا يشمل CD4 و CD8 T الاعتراف خلية المباشر واستهداف الأجانب الببتيد MHC قدمها الخلايا المشتقة من الكسب غير المشروع، CD4 غير المباشر (وربما CD8) T الاعتراف خلية واستهداف alloantigens المستمدة من الكسب غير المشروع الذي قدمه مستضد المتلقي تقديم الخلايا، والأضداد الاعتراف بوساطة من alloantigens على سطوح الخلايا الوعائية 8. ومع ذلك، فإن استجابة الأوعية الدموية للإصابة في كامل التجارب MHC متطابقة قد يكون مختلفا عن ذلك الذي لوحظ سريريا. أظهر جونسون وآخرون. 9 أنه في ترقيع مداخلة الأبهر زرعها عبر كامل الحاجز MHC عدم تطابق، ومعظم منالخلايا neointimal من أصل المتلقي وليس من أصل المانحة. وهذا يختلف عن تلك التي لوحظت في عمليات زرع الإنسان حيث معظم خلايا العضلات الملساء باطنة من أصل المانحة 9،10. لحساب هذا القيد، وقد وضعت نماذج تجريبية البديلة التي تشمل تطعيم عبر الطفيفة عدم التطابق التوافق النسيجي المستضد التي تثير ردود الأوعية الدموية التي تشبه على نحو أوثق تلك التي لوحظت في زرع السريري 11. في حين أن هذه النماذج البديلة تسمح الاستنتاجات الهامة التي ينبغي اتخاذها بشأن الردود الأوعية الدموية التي تدفع تطوير TA، والعمليات المناعية التي تسبب رفض الأوعية الدموية في القصر مستضد التوافق النسيجي الطعوم غير متطابقة تماما لا إعادة الاستسلام، تلك التي تحدث في إعداد سريرية. على سبيل المثال، يتم الاعتراف مستضدات التوافق النسيجي طفيفة سيئة من قبل الكسب غير المشروع الأجسام المضادة التفاعل 12. وبالنظر إلى الاعتبارات المذكورة أعلاه، فإنه من المهم النظر في questi المرضيةعلى يجري بحثها عند اختيار نوع المستضد عدم تطابق المستخدمة في نموذج مداخلة الأبهر. نحن هنا وصف بروتوكول مفصلة عن الفئران الأبهر مداخلة التطعيم. وصفنا مداخلة التطعيم بين الفئران كاملة MHC-متطابقة ولكن يتم استخدام نفس البروتوكول للتطعيم عبر مستضد سلالات الفئران غير متطابقة الأخرى.

<table><tbody><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>Ketamine Hydrochloride Injection USP 100 mg/ml</td><td>Ketalean</td><td>DIN 00612316</td><td></td></tr><tr><td></td><td></td><td></td><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&amp;nbsp;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, 1,000 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&amp;rsquo;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>T4A10Q07</td><td></td></tr><tr><td>Suture, 10-0 suture, 70 microns</td><td>Corporation</td><td></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 28 G 1/2</td><td>BD</td><td>REF 309309</td><td></td></tr><tr><td>25 G 7/8, hypodermic needle</td><td>BD</td><td>REF 305124</td><td></td></tr><tr><td>27 G 1/2, hypodermic needle</td><td>BD</td><td>REF 305109</td><td></td></tr><tr><td>Colibri Retractor- 1.5 cm spread 4 cm</td><td>Fine Science Tools</td><td>17000-04</td><td></td></tr><tr><td>S&amp;amp;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&amp;amp;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.

في هذا النموذج، وموسط الشريان الأورطي البطني من ماوس BALB / cYJ في الشريان الأورطي infrarenal من C57BL / 6 المتلقي. هذا يسمح بإجراء تقييم شامل لمنيع للمستضد الخيفي الردود التي تستهدف الشرايين المزروع. المناعية إصابة الأوعية الدموية في هذا النموذج يبادر الردود تعويضية الأوعية الدموية التي تبلغ ذروتها في سماكة باطنة، تضيق اللمعية وتجنيد الخلايا المناعية (الشكلان 1 و 2). هذه المعايير ثم يكون بمثابة التدريجي قراءة لشدة منيع للمستضد الخيفي الردود، رفض الأوعية الدموية، وTA. نجاح العملية يمكن تقييمها من خلال تطوير قوية سماكة باطنة الشريان شرائح المزروع وغياب باطنة سماكة في الضوابط طعم إسوي. سريريا المناعة ذات الصلة يمكن استخدامها مع هذا النموذج إلى أكثر شبها زرع السريري. كما يمكن استخدام هذا النموذج مع حيوانات معدلة وراثيا لدراسة تأثير بروتينات معينة / مسارات في منيع للمستضد الخيفي الردود علىالصورة فعلنا 14. المزروع قطاعات الأبهر تطوير باطنة سماكة تم فحص كمية المزروع تلف الأوعية الدموية بوساطة المناعة عن طريق قياس سماكة باطنة واللمعية تضيق الأبهر في قطاعات المطعمة في يوم 30 بعد الزرع. شرائح الشريان المزروع تطوير سماكة باطنة كبيرة وانسداد اللمعية ولم يلاحظ أي تغييرات في طعم إسوي قطاعات الشريان التحكم (الشكل 1). تراكم الكريات البيض في قطاعات الأبهر المزروع. تم فحص تراكم الكريات البيض في الشرايين المزروع عن طريق قياس عدد خلايا CD4 T، خلايا CD8 T، والضامة (ماك-3) 15 قبل المناعية. وقد استخدم ماك 3 وصمة عار لالضامة في هذه الدراسة على الرغم من علامات أخرى مثل F4 / 80، ويمكن أيضا أن تستخدم 16. خلايا CD4 T، تم الكشف عن خلايا CD8 T والضامة في<html> البطانية الشرايين المزروع (الشكل 2) <img alt="الشكل 1" src="/files/ftp_upload/52800/52800fig1.jpg" /> الشكل 1: تحليل النسيجي الشرايين المطعمة (A) وموسط قطاعات الشريان الأورطي البطني من مسانج والفئران خيفي في aortas البطن مقطوعة من C57BL / 6 الفئران. كانت تحصد الشرايين المطعمة في يوم 30 بعد الزرع. وترد photomicrographs تمثيلية من فان مرونة الشرايين جيسين الملون. شريط النطاق = 0.1 مم = 100 ميكرون (B) رسم بياني يصور كيف يتم قياس طبقات مختلفة من السفينة، L: التجويف، E: الطبقة البطانية، I: البطانية، M: وسائل الإعلام، A: البرانية (C) الكمي ل البطانية / نسبة وسائل الإعلام و٪ اللمعية تضييق من 30 يوما مسانج (ن = 3) وخيفي (ن = 6) زرع، * P &lt;0.05.= &quot;_ فارغة&quot;&gt; اضغط هنا لمشاهدة نسخة أكبر من هذا الرقم. <img alt="الرقم 2" src="/files/ftp_upload/52800/52800fig2.jpg" /> الشكل 2: تراكم الخلايا المناعية في الشرايين المزروع. photomicrographs التمثيلية للالمزروع قطاعات الأبهر ملطخة immunohistochemically ل(A) CD4، (B) CD8، و (C) ماك 3 و counterstained مع الهيماتوكسيلين ترد. مقياس شريط = 0.1 مم = 100 ميكرون. <a href="https://www.jove.com/files/ftp_upload/52800/52800fig2large.jpg" target="_blank">الرجاء انقر هنا لمشاهدة نسخة أكبر من هذا الرقم.</a>

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.

نموذج الفأر من منيع للمستضد الخيفي الناجم عن رفض الأوعية الدموية وزراعة تصلب الشرايين

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

mouse-model-alloimmune-induced-vascular-rejection-transplant

Universidad San Sebastian

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JoVE Journal

Medicine

8.4K Views.  Simon Fraser University. 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. 

Video: Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis

Orthotopic Aortic Transplantation: A Rat Model to Study the Development of Chronic Vasculopathy

Research models of chronic rejection are essential to investigate pathobiological and pathophysiological processes during the development of transplant vasculopathy (TVP).
The commonly used animal model for cardiovascular chronic rejection studies is the heterotopic heart transplant model performed in laboratory rodents. This model is used widely in experiments since Ono and Lindsey (3) published their technique. To analyze the findings in the blood vessels, the heart has to be sectioned and all vessels have to be measured.
Another method to investigate chronic rejection in cardiovascular questionings is the aortic transplant model (1, 2). In the orthotopic aortic transplant model, the aorta can easily be histologically evaluated (2). The PVG-to-ACI model is especially useful for CAV studies, since acute vascular rejection is not a major confounding factor and Cyclosporin A (CsA) treatment does not prevent the development of CAV, similar to what we find in the clinical setting (4). A7-day period of CsA is required in this model to prevent acute rejection and to achieve long-term survival with the development of TVP.
This model can also be used to investigate acute cellular rejection and media necrosis in xenogeneic models (5).

This video demonstrates the orthotopic aortic transplant model as a simple model to study the development of transplant vasculopathy (TVP) in rats.

زرع مثلي الأورطي : نموذج الفأر لدراسة تطوير المزمنة اعتلال وعائي

Research models of chronic rejection are essential to investigate pathobiological and pathophysiological processes during the development of transplant ...

Orthotopic Aortic Transplantation in Mice for the Study of Vascular Disease

Vascular procedures involving anastomoses in the mouse are generally thought to be difficult and highly dependent on the skill of the individual surgeon. This is largely true, but there are a number of important principles that can reduce the difficulty of these procedures and enhance reproducibility. Orthotopic aortic transplantation is an excellent procedure in which to learn these principles because it involves only two end-to-end anastomoses, but requires good suturing technique and handling of the vessels for consistent success. This procedure begins with the procurement of a length of abdominal aorta from a donor animal, followed by division of the native aorta in the recipient. The procured aorta is then placed between the divided ends of the recipient aorta and sutured into place using end-to-end anastomoses. To accomplish this objective successfully requires a high degree of concentration, good tools, a steady hand, and an appreciation of how easily the vasculature of a mouse can be damaged, resulting in thrombosis. Learning these important principles is what occupies most of the beginner's time when learning microsurgery in small rodents. Throughout this protocol, we refer to these important points. This model can be used to study vascular disease in a variety of different experimental systems1-8. In the context shown here, it is most often used for the study of post-transplant vascular disease, a common long-term complication of solid organ transplantation in which intimal hyperplasia occurs within the allograft. The primary advantage of the model is that it facilitates quantitative morphometric analyses and the transplanted vessel lies contiguous to the endogenous vessel, which can serve as an additional control9. The technique shown here is most often used for mice weighing 18-25 grams. We have accumulated most of our experience using the C57BL/6J, BALB/cJ, and C3H/HeJ strains.

We describe a technique in which a section of the abdominal aorta from a mouse is transplanted orthotopically to just below the renal arteries in an allogeneic or syngeneic recipient. This technique can be useful in studies in which transplantation of large arteries of uniform size is deemed advantageous.

زرع مثلي الشريان الأورطي في الفئران لدراسة أمراض الأوعية الدموية

Vascular procedures involving anastomoses in the mouse are generally thought to be difficult and highly dependent on the skill of the individual surgeon. ...

Mouse Models for Graft Arteriosclerosis

Graft arteriosclerois (GA), also called allograft vasculopathy, is a pathologic lesion that develops over months to years in transplanted organs characterized by diffuse, circumferential stenosis of the entire graft vascular tree. The most critical component of GA pathogenesis is the proliferation of smooth muscle-like cells within the intima. When a human coronary artery segment is interposed into the infra-renal aortae of immunodeficient mice, the intimas could be expand in response to adoptively transferred human T cells allogeneic to the artery donor or exogenous human IFN-&gamma; in the absence of human T cells. Interposition of a mouse aorta from one strain into another mouse strain recipient is limited as a model for chronic rejection in humans because the acute cell-mediated rejection response in this mouse model completely eliminates all donor-derived vascular cells from the graft within two-three weeks. We have recently developed two new mouse models to circumvent these problems. The first model involves interposition of a vessel segment from a male mouse into a female recipient of the same inbred strain (C57BL/6J). Graft rejection in this case is directed only against minor histocompatibility antigens encoded by the Y chromosome (present in the male but not the female) and the rejection response that ensues is sufficiently indolent to preserve donor-derived smooth muscle cells for several weeks. The second model involves interposing an artery segment from a wild type C57BL/6J mouse donor into a host mouse of the same strain and gender that lacks the receptor for IFN-&gamma; followed by administration of mouse IFN-&gamma; (delivered via infection of the mouse liver with an adenoviral vector. There is no rejection in this case as both donor and recipient mice are of the same strain and gender but donor smooth muscle cells proliferate in response to the cytokine while host-derived cells, lacking receptor for this cytokine, are unresponsive. By backcrossing additional genetic changes into the vessel donor, both models can be used to assess the effect of specific genes on GA progression. Here, we describe detailed protocols for our mouse GA models.

We describe protocols for our mouse graft arteriosclerois (GA) models which involve interposition of a mouse vessel segment into a recipient of the same inbred strain. By backcrossing additional genetic changes into the vessel donor, the model can assess the effect of specific genes on GA.

نماذج الماوس لتصلب الشرايين الكسب غير المشروع

Graft arteriosclerois (GA),  also called allograft vasculopathy, is a pathologic lesion that develops over  months to years in transplanted organs ...

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 replicates both the technical and pathological processes that occur in human renal transplantation. Although mouse models of allogeneic rejection in organs other than the kidney exist, and are more technically feasible, there is evidence that different organs elicit disparate rejection modes and dynamics, for instance the time course of rejection in cardiac and renal allograft differs significantly in certain strain combinations. This model is an attractive tool for many reasons despite its technical challenges. As inbred mouse strain haplotypes are well characterized it is possible to choose donor and recipient combinations to model acute allograft rejection by transplanting across MHC class I and II loci. Conversely by transplanting between strains with similar haplotypes a chronic process can be elicited were the allograft kidney develops interstitial fibrosis and tubular atrophy. We have modified the surgical technique to reduce operating time and improve ease of surgery, however a learning curve still needs to be overcome in order to faithfully replicate the model. This study will provide key points in the surgical procedure and aid the process of establishing this technique.

Here, we present a protocol to study the immunology of rejection. The surgical model presented reports a short operating time and a concise technique. Depending on the donor-recipient strain combination, the transplanted kidney may develop acute cellular rejection or chronic allograft damage, defined by interstitial fibrosis and tubular atrophy.

الماوس زرع الكلى: نماذج من طعم خيفي رفض

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

In Vitro and In Vivo Assessment of T, B and Myeloid Cells Suppressive Activity and Humoral Responses from Transplant Recipients

The main concern in transplantation is to achieve specific tolerance through induction of regulatory cells. The understanding of tolerance mechanisms requires reliable models. Here, we describe models of tolerance to cardiac allograft in rat, induced by blockade of costimulation signals or by upregulation of immunoregulatory molecules through gene transfer. Each of these models allowed in vivo generation of regulatory cells such as regulatory T cells (Tregs), regulatory B cells (Bregs) or regulatory myeloid cells (RegMCs). In this manuscript, we describe two complementary protocols that have been used to identify and define in vitro and in vivo regulatory cell activity to determine their responsibility in tolerance induction and maintenance. First, an in vitro suppressive assay allowed rapid identification of cells with suppressive capacity on effector immune responses in a dose dependent manner, and can be used for further analysis such as cytokine measurement or cytotoxicity. Second, the adoptive transfer of cells from a tolerant treated recipient to a newly irradiated grafted recipient, highlighted the tolerogenic properties of these cells in controlling graft directed immune responses and/or converting new regulatory cells (termed infectious tolerance). These methods are not restricted to cells with known phenotypic markers and can be extended to any cell population. Furthermore, donor directed allospecificity of regulatory cells (an important goal in the field) can be assessed by using third party donor cells or graft either in vitro or in vivo. Finally, to determine the specific tolerogenic capacity of these regulatory cells, we provide protocols to assess the humoral anti-donor antibody responses and the capacity of the recipient to develop humoral responses against new or former known antigens. The models of tolerance described can be used to further characterize regulatory cells, to identify new biomarkers, and immunoregulatory molecules, and are adaptable to other transplantation models or autoimmune diseases in rodent or human.

In Vitro and In Vivo Assessment of T, B and Myeloid Cells Suppressive Activity and Humoral Responses from Transplant Recipients

Here, we present a protocol to induce tolerance in transplantation, and assess in vitro and in vivo the suppressive capacity of distinct cell subsets from the recipient and the immune status of the recipient toward donor or exogenous antigens.

في المختبر و في فيفو التقييم تي وب وخلايا النقوي النشاط القمعية واستجابات خلطيه من المتلقين زرع

The main concern in transplantation is to achieve specific tolerance through induction of regulatory cells. The understanding of tolerance mechanisms ...

Immunology and Infection

A Novel Microsurgical Model for Heterotopic, En Bloc Chest Wall, Thymus, and Heart Transplantation in Mice

Exploration of novel strategies in organ transplantation to prolong allograft survival and minimizing the need for long-term maintenance immunosuppression must be pursued. Employing vascularized bone marrow transplantation and co-transplantation of the thymus have shown promise in this regard in various animal models.1-11 Vascularized bone marrow transplantation allows for the uninterrupted transfer of donor bone marrow cells within the preserved donor microenvironment, and the incorporation of thymus tissue with vascularized bone marrow transplantation has shown to increase T-cell chimerism ultimately playing a supportive role in the induction of immune regulation. The combination of solid organ and vascularized composite allotransplantation can uniquely combine these strategies in the form of a novel transplant model. Murine models serve as an excellent paradigm to explore the mechanisms of acute and chronic rejection, chimerism, and tolerance induction, thus providing the foundation to propagate superior allograft survival strategies for larger animal models and future clinical application. Herein, we developed a novel heterotopic en bloc chest wall, thymus, and heart transplant model in mice using a cervical non-suture cuff technique. The experience in syngeneic and allogeneic transplant settings is described for future broader immunological investigations via an instructional manuscript and video supplement.

To study combined solid organ and vascularized composite allotransplantation, we describe a novel heterotopic en bloc chest wall, thymus, and heart transplant model in mice using a cervical non-suture cuff technique.

A المجهرية نموذج رواية لمنتبذ، جناح كتلة جدار الصدر، الغدة الصعترية، وزرع القلب في الفئران

Exploration of novel strategies in organ transplantation to prolong allograft survival and minimizing the need for long-term maintenance immunosuppression ...

Orthotopic Hind Limb Transplantation in the Mouse

In vivo animal model systems, and in particular mouse models, have evolved into powerful and versatile scientific tools indispensable to basic and translational research in the field of transplantation medicine. A vast array of reagents is available exclusively in this setting, including mono- and polyclonal antibodies for both diagnostic and interventional applications. In addition, a vast number of genotyped, inbred, transgenic, and knock out strains allow detailed investigation of the individual contributions of humoral and cellular components to the complex interplay of an immune response and make the mouse the gold standard for immunological research. 
Vascularized Composite Allotransplantation (VCA) delineates a novel field of transplantation using allografts to replace "like with like" in patients suffering traumatic or congenital tissue loss. This surgical methodological protocol shows the use of a non-suture cuff technique for super-microvascular anastomosis in an orthotopic mouse hind limb transplantation model. The model specifically allows for comparison between established paradigms in solid organ transplantation with a novel form of transplants consisting of various different tissue components. Uniquely, this model allows for the transplantation of a viable vascularized bone marrow compartment and niche that have the potential to exert a beneficial effect on the balance of immune acceptance and rejection. This technique provides a tool to investigate alloantigen recognition and allograft rejection and acceptance, as well as enables the pursuit of functional nerve regeneration studies to further advance this novel field of transplantation.

This novel model for orthotopic hind limb transplantation in the mouse, applying a non-suture cuff technique for super-microvascular anastomosis, provides a powerful tool for in&#160;vivo mechanistic immunological research related to vascularized composite allotransplantation (VCA).

مثلي هند الاطراف زرع في ماوس

In vivo animal model systems, and in particular mouse models, have evolved into powerful and versatile scientific tools indispensable to basic and ...

Modified Heterotopic Hindlimb Osteomyocutaneous Flap Model in the Rat for Translational Vascularized Composite Allotransplantation Research

Vascularized composite allotransplantation (VCA) is a relatively new field in the reconstructive surgery. Clinical achievements in human VCA include hand and face transplants and, more recently, abdominal wall, uterus, and urogenital transplants. Functional outcomes have exceeded initial expectations, and most recipients enjoy an improved quality of life. However, as clinical experience accumulates, chronic rejection and complications from the immunosuppression must be addressed. In many cases where grafts have failed, the causative pathology has been ischemic vasculopathy. <span style="font-size: 11pt; line-height: 115%; font-family: Arial, sans-serif; color: rgb(41, 43, 49); background-image: initial; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">The biological mechanisms of the acute and chronic rejection associated with VCA, especially ischemic vasculopathy, are important areas of research. However, due to the very small number of VCA patients, the evaluation of proposed mechanisms is better addressed in an experimental model. Multiple groups have used animal models to address some of the relevant unsolved questions in VCA rejection and vasculopathy. Several model designs involving a variety of species are described in the literature. Here we present a reproducible model of VCA heterotopic hindlimb osteomyocutaneous flap in the rat that can be utilized for translational VCA research. This model allows for the serial evaluation of the graft, including biopsies and different imaging modalities, while maintaining a low level of morbidity.

Vascularized composite allograft offers life-altering benefits to transplant recipients, but the biological causes of graft rejection and vasculopathy remain poorly understood. The rodent surgical model presented here offers a reproducible, clinically relevant model of transplantation, allowing researchers to evaluate rejection events and potential therapeutic strategies to prevent their occurrence.

المعدلة المغايرة الأوستيوميوكوتانيوس رفرف النموذج في الفئران لنقل الاوعيه الدموية المركبة المركب البحوث

Vascularized composite allotransplantation (VCA) is a relatively new field in the reconstructive surgery. Clinical achievements in human VCA include hand ...

Murine Cervical Aortic Transplantation Model using a Modified Non-Suture Cuff Technique

With the introduction of powerful immunosuppressive protocols, distinct advances are possible in the prevention and therapy of acute rejection episodes. However, only minor improvement in the long-term results of transplanted solid organs could be observed over the past decades. In this context, chronic allograft vasculopathy (CAV) still represents the leading cause of late organ failure in cardiac, renal and pulmonary transplantation.
Thus far, the underlying pathogenesis of CAV development remains unclear, explaining why effective treatment strategies are presently missing and emphasizing a need for relevant experimental models in order to study the underlying pathophysiology leading to CAV formation. The following protocol describes a murine heterotopic cervical aortic transplantation model using a modified non-suture cuff technique. In this technique, a segment of the thoracic aorta is interpositioned in the right common carotid artery. With the use of the non-suture cuff technique, an easy to learn and reproducible model can be established, minimizing the possible heterogeneity of sutured vascular micro anastomoses.

Here, we present a protocol of heterotopic aortic transplantation in mice using the non-suture cuff technique in a cervical murine model. This model can be used to study the underlying pathology of chronic allograft vasculopathy (CAV) and can help evaluate new therapeutic agents in order to prevent its formation.

نموذج زرع الشريان الاورطي لعنق الرحم من murine باستخدام تقنيه الكفة المعدلة غير الخياطة

With the introduction of powerful immunosuppressive protocols, distinct advances are possible in the prevention and therapy of acute rejection episodes. ...

A Rat Orthotopic Renal Transplantation Model for Renal Allograft Rejection

Renal allograft rejection limits the long-term survival of patients after renal transplantation. Rat orthotopic renal transplantation is an essential model to investigate the mechanism of renal allograft rejection in pre-clinical studies and could aid in the development of novel approaches to improve the long-term survival of renal allografts. Donor kidney implantation in rat orthotopic renal transplantation is commonly performed by end-to-side anastomosis to recipients' aorta and inferior vena cava. In this model, the donor's kidney was implanted using end-to-end anastomosis to the recipients' renal artery and renal vein. The donor's ureter was anastomosed to the recipient's bladder in an end-to-side 'tunnel' method. This model contributes to better healing of ureter-bladder anastomosis and increases the recipients' survival by avoiding interference with blood supply and venous reflux of the lower body. This model can be used to investigate the mechanisms of acute and chronic immune and pathologic rejection of renal allografts. Here, the study describes the detailed protocols of this orthotopic renal transplantation between rats.

The rat orthotopic renal transplantation model contributes to investigating the mechanism of renal allograft rejection. The current model increases the recipients' survival without interference with blood supply and venous reflux of the lower body using an end-to-end anastomosis of kidney implantation and an end-to-side "tunnel" method of ureter-bladder anastomosis.

نموذج زرع الكلى التقويمي للفئران لرفض اللوغراف الكلوي

Renal allograft rejection limits the long-term survival of patients after renal transplantation. Rat orthotopic renal transplantation is an essential ...