In utero Allogeneic Hematopoietic Stem Cell Transplantation to Induce Tolerance

Hajdu, K.; Tanigawara, Shingo; McLean, Lynn; Cowan, Morton J.; Golbus, Mitchell S.

doi:10.1159/000264309

Cited by 24 publications

(18 citation statements)

References 7 publications

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“…Wilcoxon signed-rank test and 2 analysis were used to analyze nonparametric data, and Student's two-tailed t test was used for the parametric data. Values (two-tailed) of p Յ 0.05 were considered significant.…”

Section: Discussionmentioning

confidence: 99%

“…Early in gestation the fetal recipient is immunoincompetent and thus unable to reject allogeneic cells. The results of in utero transplants (IUT) 5 in mice, sheep, cats, and non-human primates make it clear that transplantation during the first-or early second-trimester is essential to avoid rejection (1)(2)(3)(4)(5)(6)(7). Unfortunately, while microchimerism after IUT can readily be achieved, a major limitation is the low level of engraftment.…”

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confidence: 99%

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Multilineage Engraftment with Minimal Graft-Versus-Host Disease Following In Utero Transplantation of S-59 Psoralen/Ultraviolet A Light-Treated, Sensitized T Cells and Adult T Cell-Depleted Bone Marrow in Fetal Mice

Bhattacharyya

Chawla

Smith

et al. 2002

The Journal of Immunology

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Although engraftment following in utero stem cell transplantation can readily be achieved, a major limitation is the low level of donor chimerism. We hypothesized that a lack of space for donor cells in the recipient marrow was one of the primary reasons for failure to achieve significant engraftment, and that donor T cells could make space in an allogeneic mismatched setting. We found that 3 × 105 C57BL/6 (B6) naive CD3+ cells coinjected with B6 T cell-depleted bone marrow (TCDBM) into 14- to 15-day-old BALB/c fetuses resulted in multilineage engraftment (median, 68.3%) associated with severe graft-vs-host disease (GvHD; 62 vs 0% with TCDBM alone). When 1.5 × 105 CD4+ or CD8+ cells were used, low levels of engraftment were seen vs recipients of 1.5 × 105 CD3+ cells (2.4 ± 1.1 and 6.6 ± 3.9 vs 20.4 ± 10.4%, respectively). To test the hypothesis that proliferation of T cells in response to alloantigen resulted in GvHD and increased engraftment, we pretreated naive T cells with photochemical therapy (PCT) using S-59 psoralen and UVA light to prevent proliferation. GvHD was reduced (60–0%), but was also associated with a significant reduction in engrafted donor cells (53.4 ± 4.2 to 1.7 ± 0.5%). However, when B6 T cells were sensitized to BALB/c splenocytes, treated with PCT, and coinjected with TCDBM, there was a partial restoration of engraftment (13.3 ± 2.4% H2Kb+ cells) with only one of nine animals developing mild to moderate GvHD. In this study we have shown that PCT-treated T cells that are cytotoxic but nonproliferative can provide an engraftment advantage to donor cells, presumably by destroying host hemopoietic cells without causing GvHD.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Multilineage Engraftment with Minimal Graft-Versus-Host Disease Following In Utero Transplantation of S-59 Psoralen/Ultraviolet A Light-Treated, Sensitized T Cells and Adult T Cell-Depleted Bone Marrow in Fetal Mice

Bhattacharyya

Chawla

Smith

et al. 2002

The Journal of Immunology

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“…Although IUT has produced notable levels of hematopoietic chimerism in a sheep model [4], minimal or no engraftment has been observed in most murine models [5][6][7][8][9]. Moreover, clinical experience with IUT has yielded little or no engraftment with the exception of transplants made in fetuses suffering from certain immunodeficiencies [1,2].…”

Section: Introductionmentioning

confidence: 99%

Prevention of Graft Rejection by Donor Type II CD8<sup>+</sup> T Cells (Tc2 Cells) Is Not Sufficient to Improve Engraftment in Fetal Transplantation

Chen

Chang²,

Lee³

et al. 2004

Fetal Diagn Ther

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Objectives: Tc2 cells, a subset of CD8⁺ T cells, are able to facilitate engraftment in a murine model of postnatal allogeneic bone marrow transplantation. The purpose of this study was to evaluate whether Tc2 cells could improve engraftment in fetal transplantation. Methods: Gestational day 13 C57BL/6 (H-2^b) fetal mice were used as recipients, adult B6D2F₁ mice (C57BL/6 × DBA/2, H-2^b/d) as donors, and splenocytes from B6C3F₁ (C57BL/6 × C3H/He, H-2^b/k) mice were used as stimulators in cultures used to generate the Tc2 cells from B6D2F₁ mice. Peripheral blood chimerism was examined monthly for 3 months. Thereafter, recipients were sacrificed to evaluate the levels of peritoneal, splenic and bone marrow chimerism. The T-cell responses of recipient splenocytes to cells of host origin were measured as a proliferative response in mixed lymphocyte cultures. Results: Low levels of peripheral blood cell chimerism (<0.3%) were observed at 1 month of age, which declined further by 3 months of age. The levels of donor cells in the spleen, bone marrow and peritoneal cavity were usually not more than 0.05%. The peritoneal cavity tended to have higher levels of donor cells with 1 recipient sustaining as high as 25.03% at the age of 3 months. Higher peritoneal chimerism correlated with a lower donor-specific T-cell response. Conclusions: Transplantation of Tc2 cells was insufficient to improve bone marrow engraftment in utero, suggesting that graft rejection is not the major barrier to successful in utero transplantation. Donor cells can persist in the peritoneal cavity and might play an important role in inducing immune tolerance in fetuses.

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“…However, in various systems of postnatal hematopoietic cellular transplantation, higher cell doses have been consistently associated with higher levels of chimerism. [41][42][43][44] Several explanations have been proposed for this relationship. The most simple of these is that an increased frequency of donor hematopoietic progenitors is available for competition with host cells for engraftment.…”

Section: Discussionmentioning

confidence: 99%

Early chimerism threshold predicts sustained engraftment and NK-cell tolerance in prenatal allogeneic chimeras

Durkin

Jones

Rajesh

et al. 2008

Blood

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The failure of engraftment in human cases of in utero hematopoietic cell transplantation (IUHCT) in which no immunodeficiency exists suggests the presence of an unrecognized fetal immune barrier. A similar barrier in murine IUHCT appears to be dependent on the chimerism level and is poorly explained by a lack of T-cell tolerance induction. Therefore, we studied the effect of the chimerism level on engraftment and host natural killer (NK)-cell education in a murine model of IUHCT. The dose of transplanted cells was found to exhibit a strong correlation with both the engraftment rate and chimerism level. More specifically, a threshold level of initial chimerism (> 1.8%) was identified that predicted durable engraftment for allogeneic IUHCT, whereas low initial chimerism (< 1.8%) predicted a loss of engraftment. NK cells taken from chimeras above the "chimerism threshold" dis-

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In utero Allogeneic Hematopoietic Stem Cell Transplantation to Induce Tolerance

Cited by 24 publications

References 7 publications

Multilineage Engraftment with Minimal Graft-Versus-Host Disease Following In Utero Transplantation of S-59 Psoralen/Ultraviolet A Light-Treated, Sensitized T Cells and Adult T Cell-Depleted Bone Marrow in Fetal Mice

Multilineage Engraftment with Minimal Graft-Versus-Host Disease Following In Utero Transplantation of S-59 Psoralen/Ultraviolet A Light-Treated, Sensitized T Cells and Adult T Cell-Depleted Bone Marrow in Fetal Mice

Prevention of Graft Rejection by Donor Type II CD8<sup>+</sup> T Cells (Tc2 Cells) Is Not Sufficient to Improve Engraftment in Fetal Transplantation

Early chimerism threshold predicts sustained engraftment and NK-cell tolerance in prenatal allogeneic chimeras

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