CD26 inhibition enhances allogeneic donor-cell homing and engraftment after in utero hematopoietic-cell transplantation

Abstract

In utero hematopoietic-cell transplantation (IUHCT) can induce donor-specific tolerance to facilitate postnatal transplantation. Induction of tolerance requires a threshold level of mixed hematopoietic chimerism. CD26 is a peptidase whose inhibition increases homing and engraftment of hematopoietic cells in postnatal transplantation. We hypothesized that CD26 inhibition would increase donorcell homing to the fetal liver (FL) and improve allogeneic engraftment following IUHCT. To evaluate this hypothesis, B6GFP bone marrow (BM) or enriched hematopoietic stem cells (HSCs) were transplanted into allogeneic fetal mice with or without CD26 inhibition. Recipients were analyzed for FL homing and peripheral-blood chimerism from 4 to 28 weeks of life. We found that CD26 inhibition of donor cells results in ( IntroductionIn utero hematopoietic-cell transplantation (IUHCT) has the potential to treat many congenital hematologic and genetic disorders. 1,2 It is a nonmyeloablative approach that can, under some circumstances, achieve mixed allogeneic chimerism and associated donorspecific tolerance. [3][4][5][6] This tolerance can facilitate postnatal cellular or organ transplantations with minimal or no myeloablative or immunosuppressive conditioning. 3,4,[6][7][8][9][10][11][12][13][14][15] Although engraftment of allogeneic or xenogeneic cells has been achieved, the levels of donor-cell chimerism in most circumstances following IUHCT alone have been below what would be considered therapeutic for most target diseases. [3][4][5][6][7][16][17][18][19][20][21] Additionally, the frequency of engraftment following IUHCT of allogeneic or xenogeneic cells has also been relatively low. 3,[17][18][19]21 Thus, the ideal goal of a single in utero transplantation resulting in therapeutic levels of engraftment or a 100% frequency of donor-specific tolerance has been elusive. A significant barrier to allogeneic engraftment following IUHCT is limited space in the fetus due to host-cell competition from a robust and highly proliferative fetal hematopoeitic compartment. 22 This has been supported by the presence of high-level engraftment after IUHCT in circumstances where a competitive or survival advantage exists for donor cells. [23][24][25][26][27][28] Additionally, the inability of hematopoietic stem cells (HSCs) to home and engraft with absolute efficiency may limit donor-cell engraftment following allogeneic IUHCT. 29 Thus, strategies that selectively increase donor HSC homing and engraftment in the fetal recipient may increase both the levels and frequency of engraftment following allogeneic IUHCT.CD26/dipeptidylpeptidase IV is a membrane-bound ectopeptidase that is expressed on a subset of HSCs and early hematopoietic progenitor cells. 30,31 It cleaves dipeptides from the N terminus of polypeptide chains that contain the N-terminal X-Pro or X-Ala motif. 30,32 Among its many substrates, CD26 has been shown to have selectivity for stromal-cell-derived factor 1␣ (SDF-1␣)/CXCL12. 33 SDF-1␣ is a chemokine present at high levels in adult ...

Correction of murine hemoglobinopathies by prenatal tolerance induction and postnatal nonmyeloablative allogeneic BM transplants

“…28,33,34 Therefore, IUHCT may be applicable to any disorder, such as SCD and Thal, that can be prenatally diagnosed and treated by mixed chimerism. We previously demonstrated the ability to obtain stable allogeneic engraftment following IUHCT using donor fetal liver or BM cells in the murine SCD and Thal models.…”

“…Experimentally, IUHCT has been shown to achieve allogeneic mixed hematopoietic chimerism in multiple animal models. [22][23][24][25][26][27][28][29][30] Engraftment is primarily limited by host cell competition, and, in general, IUHCT has resulted in chimerism levels below those anticipated to be therapeutic for most target diseases. 31,32 We have previously proposed and validated in the nondiseased murine and canine models, a strategy of IUHCT for the induction of donor-specific tolerance (DST), followed by nonmyeloablative postnatal HSCT to "boost" levels of engraftment into the therapeutic range.…”

“…51 Although this advantage may allow for higher initial levels of erythroid engraftment, we do not believe that this advantage is necessary to achieve engraftment following IUHCT, as we have previously demonstrated stable macrochimeric levels of allogeneic engraftment in nondisease mouse models in which no selective advantage exists. 28 Furthermore, the purpose of the current study is to demonstrate the ability to achieve levels of donor-cell engraftment adequate for phenotypic correction of the hemoglobinopathies by a clinically relevant IUHCT-based strategy. Because the postnatal transplants are performed after the transition to b-globin production, there is no discrepant selective engraftment advantage after birth in the murine model.…”

Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types

“…Taking into consideration effects of DPP4 inhibition on enhanced homing and engraftment of mouse HSC 5,6,[26][27][28] and engraftment of human CD34…”

Devouring the Hematopoietic Stem Cell: Setting the Table for Marrow Cell Transplantation

“…Finally, two approaches to providing donor HSCs with an adhesion advantage over host HSCs have used either diprotin A, a CD26 inhibitor, 11 or prostaglandin E 2 , a Wnt signaling agonist. Prostaglandin E 2 has shown efficacy in murine and nonhuman primate models.…”