Could bone marrow transplants help make xenotransplants viable?

Question

So the immune system doesn't calibrate (for want of a better euphemism) to recognize it's own cells until fairly well along in fetal development & the major components of the immune system (antibodies, white blood cells, etc) are all produced by the bone marrow.

Those are the known details that cause me to wonder if this (below) might not be a viable approach.

Introduce the patients cells to a pig fetus before it's immune system has been set & it will be born with an immune system that recognizes both it's own cells & the patients cells as it's own.

Kill the patients own marrow (as per a normal bone marrow transplant) & transplant the pigs bone marrow into him giving him an immune system that recognizes both his cells & the pigs as it's own.

If my understanding is correct you should then be able to transplant any other organs from the pig into the patient without any tissue rejection issues.

I am only interested in the science so (any legal & moral issues aside) are there any major factors I'm unaware of to suggest this approach is a non-starter?

See Xeno: The Promise of Transplanting Animal Organs into Humans By David K. C. Cooper M.D., Robert P. Lanza M.D. Published 23 March 2000 by Oxford University Press, specifically the section on "The Induction of Chimerism Before Birth" from page 117 onward in this link.

That talks about my suggested first step (though in reverse), creating a human with immunity to cell rejection of a donor animals cells, which isn't much use to anyone who's already been born.

So I flipped the idea.

A Thymus transplant might be needed as well.

Answer 1

I feel I've enough sources & data to venture an answer on this one myself now, so here goes.

Step one: Can we produce the pig in the first place?

Fetal Inoculation With Donor Cells in Cardiac Xenotransplantation 1996

Perinatal induction of immunotolerance to cardiac and pulmonary allografts July 1997

Induction of donor-specific tolerance to cardiac xenografts in utero: 1998 Sep

Cell Transplantation January 1 2003

IMMUNO-INTERVENTION FOR THE INDUCTION OF TRANSPLANTATION TOLERANCE THROUGH MIXED CHIMERISM: 2011 Aug 11

In utero hematopoietic cell transplantation: induction of donor specific immune tolerance and postnatal transplants: 2014 Nov 12

another link to the same article

In utero hematopoietic cell transplantation: induction of donor specific immune tolerance and postnatal transplants 12 November 2014

First human-pig 'chimera' created in milestone study 26 Jan 2017

Interspecies Chimerism with Mammalian Pluripotent Stem Cells 2018 Jan 26

Interspecies Chimeras and the Generation of Humanized Organs 3 Jan 2019

Yes, an animal can be produced with donor specific tolerance to the patients organs, it's a known procedure & observed effect that has been replicated numerous times in experiments, its immune system would not attack either the patients cells or its own.

Step two : Can we transplant this animals bone marrow to the patient?

Stem cell and bone marrow transplants

Yes, bone marrow transplants involving the complete removal of the original bone marrow is a long established procedure for the treatment of leukaemia.

And now being used for treatment of other severe autoimmune diseases in a way which may make this idea moot, I'll have to look into that further, not read that article in full yet.

Step three : Will we then be able to transplant other organs from this (or a genetically identical) animal to the patient without tissue rejection?

The immune system isn't seated entirely in the bone marrow & its products (the thymus, spleen & lymphatic system also have roles) so for best results some of these may also need to be replaced.

If so it must be hopped the lymph nodes play no role in in the development & tuning of the immune system, there are 500-600 of them around the body so replacing them all would be no small task.

Conclusion :

Still in progress / just saving work so far

Answer 2

No, this will likely never work - but chimeric trans plantations of 'humanised' organs might become possible.

Firstly, the process of injecting human/patient cells into an embryo would - if it works - create a chimera. Experiments of creating pig-human chimeras have (to my surprise) actually been performed, however the amount of humans cells that didn't immediately kill the embryos was very low (~0.001%), so even if they embryos would be able to reach adulthood (which the researchers didn't test) the organs wouldn't be human-like enough to allow transplantation. (source1, source2)

If the chimeric embryo's indeed survive then it might be possible to create animals that have a completely 'human' bone marrow that can be transplanted, by removing part of the pig genome that allows for the generation of bone marrow so that the injected human cells take over that role (this technique has been used successfully in rats & mice for other organs). If organs other than the bone marrow could be 'humanised' this way in pig chimeras is probably unclear since the difference between pig and human is much larger than mice and rat and might cause immune rejection issues.

Transplanting actual chimeric organs will likely never be done, since some of the cells will always be of the 'wrong' species, which would cause a lot of immune issues in some way. Since chimeras unlike hybrids will never have individual cells that combine two species, it will also not be possible to make a thymus that 'trains' the whole immune system against two species - individual T-cells might only see one type of species during maturation and therefore cause immune reactions later on.