Host Immune Rejection, continued

In response to the presence of an alien, non-self organ, the human host’s immune system goes on high alert, secreting and distributing circulating complement proteins. As indicated by the name, complement proteins play an instrumental immune-assisting role manifested by forming “membrane attack complexes,” which can damage host cells, tissues, and organs. To this end, several complement protein regulator genes were inserted (or knocked in) to tone down the host immune reaction of the xeno organ. These include CD46, CD47, CD55, and CD59, which engage in diversified activities to tame complement reaction and contribute to reduced host rejection.²⁹

To prevent the pig’s heart from outgrowing the human chest, a pig growth gene was also deleted using CRISPR/Cas9. Besides manipulation of genes via deletion or insertion, the patient was also prescribed two lines of medications. One involved intravenous immunoglobulins, known as IVIG, to tame potential infection. The other involved an experimental monoclonal antibody, KPL-404, an immune suppressant drug manufactured by Kiniksa Pharmaceuticals, a US company in Lexington, Massachusetts.²⁹ KPL-404 is an antibody-drug preparation that binds to the co-stimulatory molecule called CD40. Under ordinary circumstances, CD40 activity is a critical step in mediating B lymphocyte activation. By sequestering CD40, KPL-404 effectively blocks B cell activation, which prevents the production of antibodies that would contribute to host organ rejection.

Note: Despite the successful transplantation surgery, the patient passed away two months post-transplantation. Many unanswered questions range from the necessity or the adequacy of the genes selected for CRISPR/Cas9 removal, the efficacy of the experimental immunosuppressant drug, and whether IVIG inadvertently contributed to deteriorating post-transplantation host immune rejection states.³⁰ Lessons learned from this endeavor will help shed light on more methodical experimental designs and applications.

In September of 2023, a second pig heart transplant took place, again at the University of Maryland School of Medicine.³¹ This time, a new drug called tegoprubart (anti-CD40L) was used to bind to the CD40 instead of the KPL-404 used previously. The patient lived for nearly six weeks.

29. Wang, W., He, W., Ruan, Y., & Geng, Q. (2022). First pig-to-human heart transplantation. Innovation(Cambridge (Mass.)), 3(2), 100223. https://doi.org/10.1016/j.xinn.2022.100223
30. Kotz, D. (2023, June 30). Lessons Learned from World’s First Successful Transplant of Genetically-Modified Pig Heart into Human Patient. University of Maryland School of Medicine. https://www.medschool.umaryland.edu/news/2023/lessons-learned-from-worlds-first-successful-transplant-of-genetically-modified-pig-heart-into-human-patient-.html
31. Lewis, T. (2023, October 18). Milestone pig-to-human heart transplant may pave the way for broader trial. Scientific American. https://www.scientificamerican.com/article/milestone-pig-to-human-heart-transplant-may-pave-the-way-for-broader-trial/