Hematopoietic chimerisms: friends or foes?

Abstract

In humans, chimerisms (Chs) can occur naturally or be induced through artificial means. Feto-maternal Chs are natural and result from the spontaneous trafficking of hematopoietic or other types of cells across the placenta during pregnancy. These Chs can be transient or persist for many years and even decades. Mixed hematopoietic Chs (MHChs) can also be artificially induced, and they might have profound effects on the modulation of the immune system, which can be used for inducing donor-specific tolerance in recipients of allogeneic organ transplantation. Nonetheless, the main obstacle for the establishment of such Chs is that they require the engraftment of donor hematopoietic cells, which at present can only be accomplished using relatively toxic regimens that preclude its widespread use and currently restricts its application to some special patients, in which both a solid organ (e.g. a renal allograft) and a marrow transplantation are necessary. However, it is likely that less toxic strategies are developed that can be clinically applicable in the next decade to induce tolerance in organ transplantation. A variant of Chs is the molecular Chs, in which a proportion of the hematopoietic cells would be transduced to express a transgene (e.g. encoding a therapeutic protein, an auto-antigen, or an allergen), so that specific tolerance to these molecules is induced. This might have therapeutic applications in fields such as replacement and genetic therapies, autoimmune diseases, or allergy. Keywords: Mixed hematopoietic chimerism; feto-maternal chimerism; immune tolerance; hematopoietic transplantation; organ transplantation; molecular chimerism (Published: 25 September 2014) Citation: Advances in Regenerative Biology 2014, 1 : 24429 - http://dx.doi.org/10.3402/arb.v1.24429 Abstract in popular science Chimeras are mythological creatures composed of a lion, a snake, and a goat. In biology, chimeras refer to individuals composed of two or more types of genetically distinct cells that derive from different fertilized eggs. Some chimerisms (Chs) occur spontaneously, such as the feto-maternal Chs, which are very common and are due to the bidirectional pass of blood cells through the placenta. These Chs can be transient or they may persist for decades and contribute to the generation of different tissues. Although these Chs have been reported to be associated with a higher risk of certain diseases (e.g. fetal Ch and scleroderma in the mother), the biological role and the clinical significance of feto-maternal Chs are uncertain. When the Chs are caused only by blood cells (e.g. hematopoietic stem cells), they are called mixed hematopoietic Chs (MHChs). These MHChs can be created artificially as occurs in patients with leukemia or non-malignant diseases undergoing hematopoietic transplantation. Indeed, these patients usually become full quimeras (which means that 100% of their blood cells will be donor-derived for the rest of their lives). However, for the donor stem cells to engraft, the recipients must receive a therapy that eliminates (ablates) their own hematopoietic cells. A main limitation of these preparatory therapies (conditioning) is their high toxicity. However, since the creation of MHChs only requires a partial ablation, it can be done using less toxic conditioning regimens. The main clinical interest of MHChs is that they result in donor-specific immune tolerance, as both types of immune cells (donor and recipient) will be educated in a peaceful coexistence. So, although the conditioning regimens still need to be refined, such MHChs can be used to induce tolerance in recipients of organ transplantation, which no longer will require immunosuppressive drugs. In an analogous manner, Chs can be created using autologous hematopoietic cells that have been genetically modified with gene therapy vectors to produce a therapeutic protein, an autoantigen, or an allergen, so that a very robust tolerance to these molecules can be induced. This has potential applications in fields such as replacement and genetic therapies, autoimmune diseases, or allergy.