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Ann Thorac Surg 2001;72:745-746
© 2001 The Society of Thoracic Surgeons

Invited commentary

Bruce R. Rosengard, MDa

a Division of Cardiothoracic Surgery, University of Pennsylvania Health System, 6 Silverstein, 3400 Spruce St, Philadelphia, PA 19104, USA

e-mail: brosengard{at}mail.med.upenn.edu

Naturally occurring hematopoietic chimerism was first documented by Ray Owen in bovine dizygotic twins, which share a placental circulation [1]. Billingham, Brent, and Medawar found that these non-identical twins would accept reciprocal skin grafts, which was the first demonstration that hematopoietic chimerism was related to transplantation tolerance [2, 3]. In a Nobel Prize winning study, they modeled this experiment of nature by injecting neonatal mice with allogeneic splenocytes and found that chimeras could accept skin grafts from mice of the same strain as the cellular inoculum [4]. Sachs and Ildstad extended this observation by creating chimeras using mixed allogeneic bone marrow transplantation, in which the marrow inoculum contained both host and donor elements. Mixed chimerism avoided the immunoincompetence observed in full chimeras due to the lack of antigen presenting cells bearing the alloantigen on host thymic stromal cells, which is the protein that T cells are educated to see as self. Sachs and Ildstad showed this approach to also be successful in the context of rat-to-mouse xenotransplantation.

The study by Mohiuddin and associates is an elegant demonstration of the limitation of creating fully xenogeneic chimeras. Their study clearly documents the immunoincompetence that exists when the bone marrow inoculum used to induce chimerism bears only donor cells. Their study shows that third party grafts enjoy prolonged survival in fully xenogeneic chimeras, which is evidence of immunoincompetence. This study demonstrates the importance of the mixed chimerism approach.

Although studies involving xenogeneic mixed chimerism have demonstrated the proof of principle, most have been performed in rodents, in which both donors and recipients express {alpha}-Gal. The authors correctly point out that this is a limitation of their study and others. Pigs, the most likely source of donor organs for man, are {alpha}-Gal positive and humans lack {alpha}-Gal and have high titers of natural antibody against this carbohydrate moiety, which are responsible both for hyperacute rejection and acute vascular rejection (delayed xenograft rejection). However, the development of {alpha}-Gal knockout mice has permitted several rodent studies, which more appropriately reflect the clinical situation.

Although mixed xenogeneic chimerism is a strategy with much promise, getting porcine bone marrow or stem cells to engraft permanently in primates has not been accomplished. Moreover, concerns regarding zoonotic infection are significant. For these reasons, xenotransplantation to treat end-stage heart and lung disease is far from clinical applicability.

References

  1. Owen R.D. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 1945;102:400-401.[Free Full Text]
  2. Anderson D., Billingham R.E., Lampkin G.H., Medawar P.B. The use of skin grafting to distinguish between monozygotic and dizygotic twins in cattle. Heredity 1951;5:379-397.
  3. Billingham R.E., Lampkin G.H., Medawar P.B., Williams H.L.L. Tolerance to homografts, twin diagnosis, and the freemartin condition in cattle. Heredity 1952;6:201-212.
  4. Billingham R.E., Brent L., Medawar P.B. Actively acquired tolerance to foreign cells. Nature 1953;172:603-606.[Medline]




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