In Utero Bone Marrow Transplantation Induces Kidney Allograft Tolerance Across a Full Major Histocompatibility Complex Barrier in Swine

Lee, Patricia W.; Cina, Robert A.; Randolph, Mark A.; Arellano, Ron; Goodrich, Jennifer; Rowland, Haley; Huang, Christene A.; Sachs, David H.; Kim, Heung Bae

doi:10.1097/01.tp.0000161247.61727.67

Cited by 42 publications

(26 citation statements)

References 22 publications

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“…These results are consistent with numerous previous reports that hematopoietic chimerism observed naturally in twin gestations (30) and following in utero transplantation in multiple animal models (3,5,14,31,32) and in humans (33) can lead to donor-specific tolerance. Thus, fetal tolerance induction for stem cell transplantation remains an important and approachable clinical goal.…”

Section: Discussionsupporting

confidence: 82%

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

Nijagal¹,

Wegorzewska²,

Jarvis³

et al. 2011

J. Clin. Invest.

126

133

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Transplantation of allogeneic stem cells into the early gestational fetus, a treatment termed in utero hematopoietic cell transplantation (IUHCTx), could potentially overcome the limitations of bone marrow transplants, including graft rejection and the chronic immunosuppression required to prevent rejection. However, clinical use of IUHCTx has been hampered by poor engraftment, possibly due to a host immune response against the graft. Since the fetal immune system is relatively immature, we hypothesized that maternal cells trafficking into the fetus may pose the true barrier to effective IUHCTx. Here, we have demonstrated that there is macrochimerism of maternal leukocytes in the blood of unmanipulated mouse fetuses, with substantial increases in T cell trafficking after IUHCTx. To determine the contribution of these maternal lymphocytes to rejection after IUHCTx, we bred T and/or B cell-deficient mothers to wild-type fathers and performed allogeneic IUHCTx into the immunocompetent fetuses. There was a marked improvement in engraftment if the mother lacked T cells but not B cells, indicating that maternal T cells are the main barrier to engraftment. Furthermore, when the graft was matched to the mother, there was no difference in engraftment between syngeneic and allogeneic fetal recipients. Our study suggests that the clinical success of IUHCTx may be improved by transplanting cells matched to the mother.

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Section: Discussionsupporting

confidence: 82%

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

Nijagal¹,

Wegorzewska²,

Jarvis³

et al. 2011

J. Clin. Invest.

126

133

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“…In the murine model of allogeneic IUHCT, when transplants have been performed at E14-E15, numerous studies have reported failure of engraftment or of only microchimerism (26-34), inconsistent or absent tolerance induction (26,31,35), or immunization to alloantigen after IUHCT (30,33). Similarly, studies of organ transplantation after IUHCT with minimal levels of chimerism in large animal studies have shown an absence of tolerance (36), incomplete tolerance (37), or donor-specific tolerance (38). Interpretation of the results from both the murine and large animal studies has been complicated by marginal levels of engraftment or concerns about inconsistent delivery of donor cells to the fetus.…”

Section: Discussionmentioning

confidence: 99%

Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice

Merianos¹,

Tiblad²,

Santore³

et al. 2009

J. Clin. Invest.

114

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The lack of fetal immune responses to foreign antigens, i.e., fetal immunologic tolerance, is the most compelling rationale for prenatal stem cell and gene therapy. However, the frequency of engraftment following in utero hematopoietic cell transplantation (IUHCT) in the murine model is reduced in allogeneic, compared with congenic, recipients. This observation supports the existence of an immune barrier to fetal transplantation and challenges the classic assumptions of fetal tolerance. Here, we present evidence that supports the presence of an adaptive immune response in murine recipients of IUHCT that failed to maintain engraftment. However, when IUHCT recipients were fostered by surrogate mothers, they all maintained long-term chimerism. Furthermore, we have demonstrated that the cells responsible for rejection of the graft were recipient in origin. Our observations suggest a mechanism by which IUHCT-dependent sensitization of the maternal immune system and the subsequent transmission of maternal alloantibodies to pups through breast milk induces a postnatal adaptive immune response in the recipient, which, in turn, results in the ablation of engraftment after IUHCT. Finally, we showed that non-fostered pups that maintained their chimerism had higher levels of Tregs as well as a more suppressive Treg phenotype than their non-chimeric, non-fostered siblings. This study resolves the apparent contradiction of induction of an adaptive immune response in the pre-immune fetus and confirms the potential of actively acquired tolerance to facilitate prenatal therapeutic applications.

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“…[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.…”

mentioning

confidence: 99%

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

Peranteau

Endo

Adibe

et al. 2006

Blood

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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 ...

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In Utero Bone Marrow Transplantation Induces Kidney Allograft Tolerance Across a Full Major Histocompatibility Complex Barrier in Swine

Cited by 42 publications

References 22 publications

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice

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

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