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

The Center for Fetal Research, Children's Hospital of Philadelphia, Abramson Research Bldg, Rm 1116B, 3615 Civic Center Blvd, Philadelphia, PA 19104-4318, USA.
Blood (Impact Factor: 10.45). 01/2007; 108(13):4268-74. DOI: 10.1182/blood-2006-04-018986
Source: PubMed


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 donor-cell 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 (1) increased homing of allogeneic BM and HSCs to the FL, (2) an increased number of injected animals with evidence of postnatal engraftment, (3) increased donor chimerism levels following IUHCT, and (4) a competitive engraftment advantage over noninhibited congenic donor cells. This study supports CD26 inhibition as a potential method to increase the level of FL homing and engraftment following IUHCT. The resulting increased donor chimerism suggests that CD26 inhibition may in the future be used as a method of increasing donor-specific tolerance following IUHCT.

Download full-text


Available from: Philip Zoltick, May 15, 2014
  • Source
    • "In addition to the abovementioned strategies, there are other possibilities for manipulating HSPCs to enhance their homing that are beyond the scope of this review. For example, based on observations that the CXCL12 interaction with CXCR4+ HSPCs is attenuated by the dipeptidyl-peptidase CD26, inhibition of CD26 on HSPCs could enhance their chemotactic responsiveness to an CXCL12 gradient 60, 61. Another interesting strategy is modification of adhesion molecules on HSPCs by ex vivo treatment with fucosyltransferase, which increases the level of fucosylation of these receptors 62. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The α-chemokine CXCL12 (stromal derived factor-1; SDF-1) and its corresponding G(αI) protein-coupled CXCR4 receptor axis play an important role in retention of hematopoietic stem progenitor cells (HSPCs) in bone marrow (BM) stem cell niches. CXCL12 has also been identified as a strong chemoattractant for HSPCs and implicated both in homing of HSPCs to BM after transplantation and in egress of these cells from BM into peripheral blood (PB). However, since CXCL12, as a peptide, is highly susceptible to degradation by proteolytic enzymes, its real biological availability in biological fluids may be somewhat limited. In this review, we will present data demonstrating that the CXCL12-CXCR4 axis is positively modulated by innate immunity-derived several external factors, ensuring that even low (near threshold) doses of CXCL12 still exert a robust chemotactic influence on HSPCs.
    Preview · Article · Jan 2013 · Theranostics
  • Source
    • "Accordingly, based on observations that the SDF-1 interaction with CXCR4 + HSPCs is attenuated by the dipeptidyl-peptidase CD26, inhibition of CD26 on HSPCs could enhance the chemotactic responsiveness to an SDF-1 gradient [7]. Another interesting strategy is modification of adhesion molecules on HSPCs by ex vivo treatment with fucosyltransferase that increases level of fucosylation of these receptors [106]. As it has been demonstrated human HSPCs after blockage of CD26 or after fucosylation of adhesion molecules home and subsequently engraft better on immunodeficient mice [104]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The α-chemokine stromal derived factor 1 (SDF-1), which binds to the CXCR4 and CXCR7 receptors, directs migration and homing of CXCR4+ hematopoietic stem/progenitor cells (HSPCs) to bone marrow (BM) and plays a crucial role in retention of these cells in stem cell niches. However, this unique role of SDF-1 has been recently challenged by several observations supporting SDF-1-CXCR4-independent BM homing. Specifically, it has been demonstrated that HSPCs respond robustly to some bioactive lipids, such as sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), and migrate in response to gradients of certain extracellular nucleotides, including uridine triphosphate (UTP) and adenosine triphosphate (ATP). Moreover, the responsiveness of HSPCs to an SDF-1 gradient is enhanced by some elements of innate immunity (e.g., C3 complement cascade cleavage fragments and antimicrobial cationic peptides, such as cathelicidin/LL-37 or β2-defensin) as well as prostaglandin E2 (PGE2). Since all these factors are upregulated in BM after myeloblative conditioning for transplantation, a more complex picture of homing emerges that involves several factors supporting, and in some situations even replacing, the SDF-1-CXCR4 axis.
    Full-text · Article · Jun 2012 · The Scientific World Journal
  • Source
    • "In the environment of this different conditioning regimen, DPPIV inhibition might be unable to affect engraftment. Furthermore, an engraftment-enhancing effect of DPPIV inhibition on allogeneic HSC has been shown so far only after myeloablative conditioning or in utero transplantation [21,22]. The potential effect on allogeneic BM engraftment after nonmyeloablative conditioning—which is of relevance for clinical BMT—has not been ascertained previously. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In order to develop minimally toxic bone marrow transplantation (BMT) protocols suitable for use in a wider range of indications, it is important to identify ways to enhance BM engraftment at a given level of recipient conditioning. CXCL12/stromal cell-derived factor-1α plays a crucial physiological role in homing of hematopoietic stem cells to BM. It is regulated by the ectopeptidase dipeptidyl peptidase IV (DPPIV; DPP4) known as CD26, which cleaves dipeptides from the N-terminus of polypeptide chains. Blocking DPPIV enzymatic activity had a beneficial effect on hematopoietic stem cell engraftment in various but very specific experimental settings. Here we investigated whether inhibition of DPPIV enzymatic activity through Diprotin A or sitagliptin (Januvia) improves BM engraftment in nonmyeloablative murine models of syngeneic (i.e., CD45-congenic) and allogeneic (i.e., Balb/c to B6) BMT (1 Gy total body irradiation, 10-15 × 10(6) unseparated BM cells/mouse). Neither Diprotin A administered in vivo at the time of BMT and/or used for in vitro pretreatment of BM nor sitagliptin administered in vivo had a detectable effect on the level of multilineage chimerism (follow-up >20 weeks). Similarly, sitagliptin did not enhance chimerism after allogeneic BMT, even though DPPIV enzymatic activity measured in serum was profoundly inhibited (>98% inhibition at peak exposure). Our results provide evidence that DPPIV inhibition via Diprotin A or sitagliptin does not improve engraftment of unseparated BM in a nonmyeloablative BMT setting.
    Full-text · Article · Nov 2011 · Experimental hematology
Show more