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In Memoriam - Agnès Marie Azimzadeh, Ph.D

Agnès Azimzadeh passed away on March 15, 2021, after a courageous battle with intestinal cancer. She leaves her devoted husband, Djavad; their sons Julien and Philippe, and Julien’s wife Rebecca; her parents, Simone and Bernard Isabey; her brother Daniel Isabey; and her family-by-affection Li Ni and Julie Lin. The scientific and clinical transplant communities she touched at Massachusets General Hospital, University of Maryland, and around the world join her family in celebrating her life, and mourning her premature loss.
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Agnès grew up in the Franche-Comté region of France. She received her Ph.D. in Molecular and Cellular Biology and Immunology from the University Louis Pasteur in Strasbourg, France (1992) under the mentorship of Dr. Marc Van Regenmortel. During her post-doctoral fellowship (1993-99) while working on xenotransplantation at Strasbourg’s Institute of Transplantation with professors Cazenave and Soulilou, she began to develop her extensive network of national and international collaborators. In 1999 she formed a 22-year scientific partnership with Richard N. Pierson III, working at Vanderbilt University (1999-2002), University of Maryland (2002-2018), and Massachusetts General Hospital (2018-2021).

Most of her scientific contributions related to translational studies conducted in primate models. Her important role in these multi-investigator collaborative studies were recognized by a “Grand Prix de Medicine” award from the Academy of Sciences of Toulouse (1997), and a Young Investigator’s Award (2002) and recognition as a Key Opinion Leader (2006) by The Transplantation Society. She was particularly recognized for her collaborative contributions to develop and apply molecular biologic techniques to monitor innate immunity, adaptive immunity, and inflammation in primate transplant models. Her work in collaboration with Dr. Pierson was funded continuously since 1999 by NIH and many other sources.

Agnès had a long-standing interest in xenotransplantation, and her diagnostic tools and the mechanistic insights they enabled have nourished steady progress in this field in the last two decades. She was part of the team that clarified the role of natural antibodies, complement, and coagulation in liver and lung xenograft rejection in the 1990’s, in particular for the first time elucidating the contribution of porcine von Willebrand’s factor (vWF) to coagulation pathway dysregulation in baboons. Her technical expertise enabled design of immunologic and molecular tools that were informative during evaluation of very expensive and rare genetically modified pigs as they were developed, and contributed to the remarkable recent progress of this field toward clinical application. Her contributions in the field of xenotransplantation were recently recognized by her election to the Presidency of the International Xenotransplantation Association (2019-21). She also studied the role of both anti-donor antibodies (alloantibodies) and auto-antibodies in the pathogenesis of chronic heart allograft rejection during blockade of the CD40, CD154, and CD28 costimulation pathways. Her work unveiled the contribution of alternative costimulatory pathways to graft injury: ICOS and CD28-driven chronic rejection occurred despite CD154 blockade that was efficient to produce ‘tolerance’ to viral antigens in the same experimental subjects. Her work with Dr. Pierson on pre-emptive B cell depletion in primates led to an NIH-funded clinical trial (CTOT-11).

Agnès wrote of herself, “I love teaching and take it very seriously”. She mentored over 40 medical students, and over 20 post-doctoral fellows, as well as countless young faculty members, many of whom are are now established as independent investigators. She was an invaluable counselor to the IXA, and selfless scientific and professional advisor to an array of international collaborators working in the field of xenotransplantation. She will perhaps be best remembered for her warmth of spirit, and her love of quality, which she found and appreciated deeply in friends, food, and science.

In lieu of flowers, the family requests that gifts be directed either to the MGH Cancer Center, in support of research, or to the IXA, in support of an awards program to be established in her memory. Agnès Azimzadeh Fund

Our Congress dates have changed! Join us virtually on September 23-25, 2021

The IPITA/IXA/CTRMS Joint Congress scheduled to take place in San Diego, October 21-25 2021 has been postponed due to the continued impact of the COVID-19 pandemic on travel and meeting guidelines. It has been rescheduled to the fall of 2023. This year’s meetings are now as follows:

IXA-CTRMS Joint Virtual Congress will be held on September 23-25, 2021

IPITA Virtual Congress will be held on October 20-23, 2021


Join the 2021 Congress!
Visit https://www.ixa-ctrms2021.org

Important dates:

  • Registration Opens: May 10, 2021

  • Abstract submission deadline: May 18, 2021

  • Submit your abstracts : Click here

Council nominations have begun – Nomination deadline is April 1!

The International Xenotransplantation Association (IXA) is requesting nominations for our upcoming Council election.

Nominations are being sought for President-Elect, Secretary-Treasurer and three (3) Councilor positions, that will commence following the 2021 IXA Virtual Congress on September 21-23 for a four-year term. *Due to the recent change in council leadership, some position may require erarlier start date

To be eligible for election the candidate must be a Full IXA Member in good standing with the Association at the time of their nomination and during their term of office. Nominations must be completed online by using your member login.

To nominate, you will need the following information:

  1. Name of the nominee (Must be a member of IXA)

  2. Names of 2 supporters (Must be a member of IXA)

  3. 200 word Bio of nominee

  4. Photo of nominee

Nominations must be completed by April 1, 2021 at 11:59 PM ET.

2020 Xeno-Prize

Joachim Hundreiser
Rabea Hein

The IXA Carl-Gustav Groth Xeno Prize is awarded annually to the first author(s) of the best paper published in the journal Xenotransplantation each year. The 2019 award went to authors Joachim Hundreiser and Rabea Hein of the Hannover Medical School (Hannover, Germany) for their manuscript entitled “Role of human and porcine MHC DRB1 alleles in determining the intensity of individual human anti-pig T-cell responses.”

In addition to the awarded authors, the paper was co-authored by Claudia Pokoyski, Antje Brinkmann, Heike Duvel, Astrid Dinke, Britta Trautewig, Janina-Franziska Siegert, Dorothee Romermann, Bjorn Petersen, and Reinhard Schwinzer.

The article demonstrates that variability in human and porcine MHC determines the intensity of individual human anti-pig T-cell responses leading to the conclusion that MHC typing and cross-matching of prospective recipients of xenografts and pig donors could be relevant to clinical xenotransplantation outcomes.

The article can be found here :

CLICK HERE

The Xeno Prize is jointly sponsored by the International Xenotransplantation Association (IXA) and Wiley, the publisher of Xenotransplantation journal, and has been awarded annually since 2012. A list of previous award recipients can be found on the IXA website following this link :

CLICK HERE

We encourage our members to submit their work for peer-reviewed publication in our official journal to become eligible for this prestigious award.

Young Investigators Eligible for New Award

This year marks the inauguration of the David K.C. Cooper Young Investigator Award. This new award will recognize a young scientist who has contributed to the field of xenotransplantation by presenting their research findings at the biennial IXA Congress. It has been generously funded by IXA member donations in direct response to members requests for additional support for our younger members.

The award is a fitting tribute to the work of Dr. Cooper, who has trained many surgeon/investigators and helped to shape the path of xenotransplantation throughout his illustrious career.

Dr. Cooper already had a full career as a successful general and cardiothoracic surgeon in the UK before deciding to concentrate his focus on xenotransplantation research in the US. He is well known as a prolific author of both peer-reviewed scientific articles and several popularly published books detailing the histories of famous medical practitioners. In recognition of his scientific achievements, Dr. Cooper has been awarded a Hunterian Professorship by the Royal College of Surgeons of England among many other honors. He has taken on roles as Honorary Secretary/Treasurer of the International Society for Heart and Lung Transplantation, Founding Honorary Secretary of the IXA, IXA President, and Editor-in-Chief of Xenotransplantation journal. Dr. Cooper was elected to Honorary Membership of the IXA in 2009. He currently occupies the position of Co-Director of the Xenotransplantation Program at the University of Alabama at Birmingham.

Complete guidelines for eligibility and award selection are listed online :

CLICK HERE

We ask that members take this opportunity to follow in the footsteps of one of the pioneers of xenotransplantation and inspire the next generation of leaders in our field by contributing to the David K.C. Cooper Award. Information on how you can contribute can be found here:

CLICK HERE

Donations are tax deductible in the US. All donations are welcome. If you cannot contribute financially at this time (and even if you can), be sure to make this award known to all eligible colleagues under the age of 45 so that they can submit their abstracts. Remember, this award is separate from the IXA/TTS Scientific (Young Investigator) Awards. Investigators can submit their work for consideration for both awards, but the same investigator cannot be awarded both prizes at the same Congress.

The first “Cooper Award” will be bestowed at the IXA/CTRMS Joint 2021 Congress, currently scheduled to meet virtually on September 23-25, 2021. Submission details will be provided as they become finalized.

The Contribution of Genetic Engineering to Xenotransplantation

As we start a new calendar year, it is interesting to look back on the strides that have been made in the field of xenotransplantation since the introduction of the earliest genetically engineered pig to be used as donors. Progress at times seem slow but 20 years ago the transplantation of a pig organ to a primate resulted in graft loss within a few minutes or hours due to hyper acute rejection (HAR). The earliest genetically engineered (GE) pigs added human complement regulatory proteins to overcome HAR. This led to survival of days to weeks until delayed xenograft rejection, which was found to be antibody mediated.

The big breakthrough in GE pigs was the development of alpha 1,3-Galactosyltransferase gene knock-out (GTKO) pigs, which eliminated the predominant pig carbohydrate to which humans had preformed antibodies against. This has led to the identification of several correspondingly lesser but still potentially important carbohydrates that contribute to graft rejection. Initially, methods of cloning and gene editing were slow and cumbersome, but ever more sophisticated methods such as CRISPR-Cas9 have allowed for more and quicker modifications. McGregor et al reported pig-to-baboon heterotopic cardiac graft survival of up to 113 days in 2004 using pigs transgenic for hCD46. The following year Yau-Lin et al reported 179-day graft function using GTKO pigs. A decade later the group of Mohiuddin et al has the place of honor, reporting graft survival of 945 days using GTKO/hCD46/hTBM pigs in an heterotopic (non-life-supporting) pig heart grafts in baboons.

In 2018, a German group described the first instance of 75% survival for up to 195 days of a life-supporting orthotopic pig heart in baboons using triple genetically-modified porcine organs, well exceeding the key requirement for clinical application of cardiac xenotransplantation as defined in 2002 by the ISHLT International Advisory Board. In the kidney, graft survival has reached almost 500 days using GTKO/CD55 pigs. Other organs have shown impressive results in nonhuman primates using multi-GE pigs as well. The synergy between the scientists generating genetically engineered pigs and those studying graft survival in xenogeneic animal models brings us to the present, where we now have the ability to utilize pigs transgenic for many more modifications, opening new realms of possibilities that did not exist just a few decades ago. Slow but steadily advancing successes lead us to anticipate clinical trials to begin perhaps as soon as the coming year. In 20 years, scientists may look back on our work today as the pioneering a new age of clinical xenotransplantation.

The FDA approves the use of genetically engineered pigs in medicine and food

On December 14, the US Food and Drug Administration (FDA) approved the use of GalSafeTM pigs, for both human consumption and as a source for potential therapeutic uses. The first dual use approval of its kind ever and a new landmark in developing genetically engineered pigs.

The FDA granted approval of the GalSafeTM pigs to Revivicor, a company based in Blacksburg, Virginia, USA that first generated (1,3) galactosyltransferase Knock-Out (GTKO) cloned pigs via nuclear transfer using adult cells to provide tissues and cells for xenotransplantation.

David Ayares, PhD, Executive Vice President and CSO of Revivicor, shares his enthusiasm for the approval of the Revivicor GalSafeTM pigs, a process that required not only advanced technology in genetic engineering but also a rigorous approach to ensure all regulatory aspects of the production complied with FDA mandates. The whole process has taken several years and significant efforts.

What is the need for such pigs?

GalSafeTM pigs lack the enzyme galactosyltransferase, which is necessary to express galactose-α-1,3-galactose (alpha-Gal) a sugar that is found on cells of all mammals with the exception of Old World monkeys and humans. In Old World monkeys and human’s exposure to alpha-Gal elicits natural anti-alpha-Gal antibodies (IgM and IgG), which are responsible for hyperacute rejection of xenografts.

The extent and consequences of the evolutional differences in alpha-Gal expression, however, turned out to be more relevant to human health than initially comprehended. In the last 5 years a body of evidence has emerged showing that alpha-Gal exposure can also elicit IgE production, thus predisposing the immune system to develop harmful allergic reactions to even minute doses of alpha-Gal, in this case a powerful allergen.

Allergies to alpha-Gal can occur via consumption of red meat, in combination with a tick bite, which then sensitizes the patient to the allergen. Known by various names such as “red meat allergy”, “tick bite allergy” or “alpha-Gal syndrome”, the consequences of this allergic response can be serious, and often life threatening. Recent studies estimated that millions of individuals in the US, EU, and Asia suffer from such conditions, and that there are areas in the world where as much as 20% of the population develop allergies to alpha-Gal, especially among individuals that spend long hours outdoors in non-urban areas. Alpha-Gal syndrome can also cause serious allergic reactions, such as anaphylaxis, to mammalian-derived medicines like heparin, or medical devices including heart valves. Consumption of GalSafeTM meat, now FDA approved, provides an alternative to traditional un-manipulated alpha-Gal expressing products, while avoiding allergic reactions to alpha-Gal.

What is the relevance of GalSafeTM approval for the xenotransplantation scientific community?

The use of genetically engineered pig donors proved to be a crucial factor in improving compatibility between donor and recipient thus enhancing graft survival in pre-clinical studies, with better results achieved using pigs with multiple genetically manipulations (currently up to 10 gene edits are under consideration for whole organ transplants). Dr. Ayares thinks that, even though GalSafeTM pigs carry only one genetic modification, the steps required for FDA approval of GalSafeTM should help set the stage to facilitate approval of multiple genetically engineered pigs for future medical endeavors. Regardless, GalSafeTM pigs may have immediate utility for xenotransplantation of heart valves, skin, neurons and pancreatic islets, which would require separate approvals as human therapeutics.

We may expect that in the near future GalSafeTM meat will be available on the market and the first question will likely be “how does it taste?” Compositional analysis (ie. protein, lipid, nutritional contents), as well as sensory studies (taste, texture), performed under GLP protocols, showed equivalence of GalSafeTM to unmodified pork, thus answering that question.

Involvement of IXA members in the 2020 ESOT Transplant Learning Journey 2.0

In 2020, IXA members played a central role in the Transplant Learning Journey 2.0 (TLJ 2.0), a virtual event devoted to transplant surgeons, physicians, coordinators, nurses and scientists, that took place in the context of the educational activities coordinated by the European Society for Organ Transplantation (ESOT).

In particular, several IXA investigators significantly contributed to the Consensus Workshop 01 (WS01), dedicated to “New surrogate endpoints in transplantation”, coordinated by Maarten Naesens and Stefan Schneeberger. Indeed, the success of clinical transplantation is still limited by the scarcity of human organs and by the immunological barrier that precludes routine long-term (>20 years) graft survival. Novel approaches currently studied very aggressively in the preclinically arena include xenotransplantation, 3D printed organs, organs grown in vitro conditions, organs recovered after ex vivo reconditioning, and immunologically impossible transplants.

At this stage, there is the need to get prepared for translation of these novel approaches into the clinic. Yet, for each of these, inclusion criteria and endpoints indispensable for evaluating efficacy in clinical trials remain largely undefined.

In particular, the extraordinary progress achieved by preclinical xenotransplantation research in the last decade has reached a stage where a consensus on clinical trial design is really needed. Accordingly, the xenotransplantation science was central to the WS01 seminars organized within TLJ 2.0. Amongst the xenotransplantation speakers, Dr. Richard ‘Robin’ Pierson held a very interesting presentation dedicated to the key endpoints that will need to be satisfied to speak about “xenotransplantation success”. ‘Robin’ also gave a talk on the ethical aspects of xenotransplantation. He discussed about known and unknown aspects of the field, risks to recipients but also care-givers and society at large, randomization and equitable access to treatments. He also wondered whether a truly informed consent would be really possible and stated that it would be probably acceptable to allow people to take the risk as long as the information available was fully shared.

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Also featured, Bruno Reichart presented the latest data of the ongoing preclinical programme in Munich, whilst Linda Scobie summarized to regulatory hurdles that will need to be overcome for the initiation of clinical trials. In this context, is it encouraging that no major hurdle seems to preclude clinical xenotransplantation although there is the need to ensure that xenotransplantation adheres to existing guidelines and directives, especially with regard to safety, quality, processing and traceability. Emanuele Cozzi and Rainer Oberbauer spoke about patient selection for xenotransplantation trials where the most likely candidates could be represented by highly sensitized patients with renal failure and poor vascular access, who would never be eligible for a human transplant.

In all cases, Robin Pierson stated his strong opinion that “desperate” patients should not be enrolled at the initial stages, to avoid both futility for the patient and obscuring possible xenograft efficacy by testing a ‘hopeless’ circumstance. The xenotransplantation discussion was also enriched by the thoughtful considerations of Kevin Fowler, a US patient advocate and a kidney recipient, who reiterated that “patient involvement was crucial for success”.

Each WS01 session was followed by a lively discussion with the contribution of attendees with different backgrounds and linked from all over the world.

A summary of the TLJ 2.0 event is accessible on the TLJ website and a consensus document on the content of the activities of the Consensus Workshop 01 (WS01), dedicated to “New surrogate endpoints in transplantation” will be prepared and submitted to Transplant International.

IXA YOUNG INVESTIGATOR COMMITTEE - CALL FOR APPLICATIONS

We are recruiting 4 new members!

Do you have new ideas and would like to engage with our association’s activities to advance the scientific and clinical mission of IXA?

Who may apply:

Eligibility: Self-motivated and dynamic Physicians, Surgeons and Scientists, Fellows or Graduate Students, Health Care or Veterinary Care providers that have an invested interest in the field of Xenotransplantation. Applicants must not yet have reached the level of Assistant Professor or an equivalent entry-level independent faculty position.

To be eligible you must be a member of IXA. If you wish to become a member, you are welcome to submit a membership application,
please see instructions here.

What to expect:
You will form lasting relationships with your peers, learn more about how scientific societies work, have your voice be heard and have a lot of fun while doing it.

You will also have responsibilities such as to organize educational activities during the year and during the biennial IXA conferences. You will be expected to be an active participant and invest some of your time to achieve the goals of the YIC. And you will find that it’s so worth it!

How to apply:
If you are interested in joining the IXA YIC please send your CV (2 pages max) and a 1-page letter to include your interests and commitment in the field, and your motivation to join the YIC, to Chris Burlak, the IXA Young Investigator Committee Chair here

Deadline for application: April 15, 2021
Effective nomination date: May 1, 2021

Requesting your opinion for a new IXA Council Communication Initiative

The IXA is diligently preparing an upcoming ongoing series of podcasts, as well as several webinars in conjunction with TTS. We hope that by instituting these new forms of communication we can further open lines of dialogue between members on topics that can enrich us all. To that point, we would like to solicit our members opinions on what topics and speakers they would like to hear in the short form podcast format or in the more traditional webinar format. Your participation will ensure that the IXA continues to satisfy the needs of our varied membership.

Please watch for the upcoming survey!

Requesting your opinion for a new IXA Council Communication Initiative

The IXA is diligently preparing an upcoming ongoing series of podcasts, as well as several webinars in conjunction with TTS. We hope that by instituting these new forms of communication we can further open lines of dialogue between members on topics that can enrich us all. To that point, we would like to solicit our members opinions on what topics and speakers they would like to hear in the short form podcast format or in the more traditional webinar format. Your participation will ensure that the IXA continues to satisfy the needs of our varied membership.

Please watch for the upcoming survey!

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Address

International Xenotransplantation Association
C/O The Transplantation Society
International Headquarters
505 Boulevard René-Lévesque Ouest
Suite 1401
Montréal, QC, H2Z 1Y7
Canada