Xenotransplantation

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Athymic mouse with implanted human prostate carcinoma (LNCaP cell line).

A xenotransplantation ( Greek  ξένος , xénos : "stranger, stranger, stranger") is the transfer of viable and functional cells or cell assemblies (including entire organs or body parts) between different species .

This must be distinguished from allografts , in which the transfer is carried out between genetically different individuals of the same species.

Because of the limited availability of donor organs for allografting, xenotransplantation promises to be a possible alternative. Pig heart valves are already used today as a possible alternative to mechanical ones. However, the heart valves are processed in such a way that they do not have any antigen on the surface that could be recognized as foreign. However, to this day, whole organ xenotransplants are not possible in humans.

Although primates are much more closely related to humans, pigs are now being traded as the most promising option for organ transplants. Pig organs are physiologically better suited to meet the requirements of the human body. The first heart xenograft on a human with a chimpanzee heart showed that the heart was too small to keep blood circulating (Hardy, Mississippi 1964). Pig hearts, on the other hand, have sufficient left ventricle function to keep a person alive and are also small enough to fit into the thorax .

Mechanisms of the rejection reaction

The rejection reaction can be roughly divided into four different periods of time:

  1. HAR
  2. AVR
  3. AHXR
  4. chronic rejection

Hyper Acute rejection (HAR - hyperacute rejection )

The first stage of the rejection reaction occurs within the first 24 hours. Antibodies that have already formed are directed against the endothelial cells of the implant. The accumulation of these IgG antibodies leads to complement activation, swelling of the endothelium and microvascular thrombosis.

The antibodies used here are directed against the Galα1, 3Galβ1, 4GlcNAc (αGal) carbohydrate side chains of the pig endothelial cells . These side chains are found on the endothelial cells of non-primate mammals as well as New World monkeys and are not present in humans and Old World monkeys . Due to natural infections of the gastrointestinal tract with αGal-expressing microorganisms, the human body forms antibodies against these carbohydrates very early on. In order to avert this type of rejection, a so-called ko pig (αGal - / -) was generated for this carbohydrate in 2002 , with which the next phases of rejection could be reached.

Acute vascular rejection (AVR )

This segment of rejection, which occurs within a few days, is similar to HAR, except that cells of the innate immune system such as NK cells, macrophages, and neutrophils are still involved.

Acute humoral xenograft rejection (AHXR )

In this phase, new antibodies against the xenograft are formed that are not directed against αGal. Here, too, both complement and the blood coagulation system are activated.

Chronic rejection

In the last experimental phase of xenotransplantation, a thrombotic microangiopathy develops .

Considerable advances have been made in the removal of antibodies from recipient blood, e.g. B. by immunoadsorption through the use of transgenic pig hearts that expressed human complement inhibitors such as hDAF ( CD55 ) but also CD46 and have no Gal sugar epitopes on the cell surfaces, so-called GalKO animals achieved with the additional use of special immunosuppressant combinations . These were the pig heart transplants in both life-sustaining models of orthotopic heart transplant to 58 days after heterotopic - thoracic xenogeneic heart transplantation up to 50 days and in the non-life-sustaining abdominal model with Kostimulationsblockade by CD40 antibody until more than two years, thereby potentially paves a breakthrough. The prerequisite for clinical use is the implementation of orthotopic or heterotopic thoracic xenogenic heart transplants in a preclinical trial with the aim of long-term survival of 90 days.

Hazards and Ethical Concerns

The greatest concern with the use of xenografts is the risk of transmitting animal pathogens to the host and to all of humanity.

For example, pigs can be infected with hepatitis E viruses, porcine cytomegaloviruses and porcine circoviruses . In addition, they also carry pig retroviruses (PERV - porcine endogenous retrovirus ) in their genome , between 3 and 140 sequences depending on the breed, some of which can actively replicate and also recombine and be transmitted. It is known that the types PERV-A and PERV-B can also infect human cell lines in laboratory tests. Therefore, xenografts from pigs pose a safety risk. However, pigs could be bred for the first time in 2017 after all 25 PERV sequences were removed from their genome using CRISPR-Cas .

There are also ethical concerns about xenotransplantation, as it creates a chimera containing living cells from two different species.

From a religious perspective, there are different concerns. At the "XVIII International Congress of the Transplantation Society" in Rome in 2000 Pope John Paul II approved the use of pigs as organ donors.

The xenotransplantation of human tissue, such as tumor cells , to test animals - in particular nude mice  - (so-called xenografts ) has been an established process in preclinical research since 1972 .

See also

literature

Web links

Wiktionary: Xenotransplantation  - explanations of meanings, word origins, synonyms, translations

Individual evidence

  1. ↑ JS Allan, GA Rose, JK Choo et al: Morphometric analysis of miniature swine hearts as potential human xenografts. In: Xenotransplantation. 8, 2001, pp. 90-93. PMID 11328578
  2. ↑ B. Sprangers, M. Waer, AD Billiau: Xenotransplantation: where are we in 2008? In: Kidney International . Volume 74, number 1, July 2008, pp. 14-21, doi: 10.1038 / ki.2008.135 . PMID 18418354 . (Review).
  3. Jump up ↑ P. Brenner, H. Reichenspurner, M. Schmoeckel, C. Wimmer, A. Rucker, V. Eder, B. Meiser, M. Hinz, T. Felbinger, J. Müller-Höcker, C. Hammer, B. Reichart : IG-therasorb immunoapheresis in orthotopic xenotransplantation of baboons with landrace pig hearts. In: transplant. Volume 69, Number 2, January 2000, pp. 208-214. PMID 10670628 .
  4. ↑ P. Brenner , H. Reichenspurner, M. Schmoeckel, C. Wimmer, A. Rucker, V. Eder, B. Meiser, M. Hinz, T. Felbinger, C. Hammer, B. Reichart: Prevention of hyperacute xenograft rejection in orthotopic xenotransplantation of pig hearts into baboons using immunoadsorption of antibodies and complement factors. In: Transpl Int. 13 Suppl 1, 2000, pp. S508-S517.
  5. ↑ P. Brenner, M. Hinz, H. Huber, M. Schmoeckel, H. Reichenspurner, B. Meiser, C. Hammer, B. Reichart: The influence of antibody and complement removal with a Ig-Therasorb column in a xenogeneic working heart model. In: Eur J Cardiothorac Surg. 15 (5), May 1999, pp. 672-679.
  6. ↑ P. Brenner, M. Schmoeckel, C. Wimmer, A. Rucker, V. Eder, S. Uchita, U. Brandl, M. Hinz, T. Felbinger, B. Meiser, C. Hammer, H. Reichenspurner, B. Reichart: Combination of hDAF-transgenic pig hearts and immunoadsorption in heterotopic xenotransplantation of immunosuppressed baboons. In: Transplant Proc. 37 (1), Jan-Feb 2005, pp. 483-486.
  7. ↑ P. Brenner, M. Schmoeckel, C. Wimmer, V. Eder, A. Rucker, T. Felbinger, S. Uchita, M. Hinz, U. Brandl, B. Meiser, H. Reichenspurner, C. Hammer, B. Reichart: Mean xenograft survival of 14.6 days in a small group of hDAF-transgenic pig hearts transplanted orthotopically into baboons. In: Transplant Proc. 37 (1), Jan-Feb 2005, pp. 472-476.
  8. ^ CG McGregor, WR Davies, K. Oi, HD Tazelaar, RC Walker, K. Chandrasekaran et al .: Recovery of cardiac function after pig-to-primate orthotopic heart transplant. In: Am J Transplant. (suppl2), 2008, p. 205.
  9. ↑ A. Bauer, J. Postrach, M. Thormann, S. Blanck, C. Faber, B. Wintersperger, S. Michel, JM Abicht, F. Christ, C. Schmitz, M. Schmoeckel, B. Reichart, P. Brenner: First experience with heterotopic thoracic pig-to-baboon cardiac xenotransplantation. In: Xenotransplantation. 17 (3), May-Jun 2010, pp. 243-249. doi: 10.1111 / j.1399-3089.2010.00587.x .
  10. ↑ B. Reichart, S. Guethoff, T. Mayr, M. Thormann, S. Buchholz, J. Postrach, D. Ayares, RB Elliott, P. Tan, A. Kind, C. Hagl, P. Brenner, JM Abicht : Discordant cardiac xenotransplantation: broadening the horizons. In: Eur J Cardiothorac Surg. 45 (1), Jan 2014, pp. 1-5. doi: 10.1093 / ejcts / ezt483 .
  11. ↑ M. Mohiuddin, P. Corcoran, A. Singh, R. Hoyt, M. Thomas, M. Eckhaus, D. Ayares, K. Horvath: Absence of thrombotic complication is a major advantage of murine anti CD40 over anti CD154 in heterotopic cardiac xenotransplantation studies. Abstract Joint Congress IXA 2011.
  12. ↑ MM Mohiuddin, PC Corcoran, AK Singh, A. Azimzadeh, RF Hoyt, Jr., ML Thomas, MA Eckhaus, C. Seavey, D. Ayares, RN Pierson, KA Horvath: B-Cell Depletion Extends the Survival of GTKO. hCD46Tg Pig Heart Xenografts in Baboons for up to 8 Months. In: American journal of Transplantation. 2011.
  13. ↑ Joachim Denner: Paving the path toward procine Organs for transplantation New England Journal of Medicine 2017, Volume 377, Issue 19 of November 9, 2017, pages 1891-1893, DOI: 10.1056 / NEJMcibr1710853
  14. ↑ JF George: Xenotransplantation: an ethical dilemma. In: Current opinion in cardiology. Volume 21, Number 2, March 2006, pp. 138-141. doi: 10.1097 / 01.hco.0000203183.81534.f9 . PMID 16470151 . (Review).