Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 109

in MHC-mismatched recipients [140] . Reasons for the different results of
studies with CD8 + TCR − CD3 + cells are not clear. Given the extreme scarcity
of the CD8 + TCR − CD3 + ClassII dim Thy1 + marrow population, translational
application will require precise isolation and expansion strategies.

Facilitating populations are assessed with regard to their ability to pro-
mote engraftment through the inhibition of recipient immune responses
against donor cells. However, these cells may influence the overall success
of engraftment by affecting responses other than immune-mediated resis-
tance. For example, several recent studies showed that after effectively elim-
inating the need for donor facilitating populations by ablative conditioning,
the addition of donor T cells to purified donor HSC resulted in poorer overall
cell recovery and lymphoid reconstitution compared to non-T-cell-contain-
ing grafts [111] . Although presently unknown, facilitating cells employed to
help overcome resistance after non-lethal conditioning might also induce
an unwanted diminution of hematopoietic recovery, perhaps through dam-
aging lympho-hematopoietic compartments in recipients after transplant.
A CD8α + TCR − facilitating cell population was recently reported to induce
both donor and recipient Treg cells, a population which itself can promote
engraftment (see next section) [143,144] . In the present context it is interest-
ing that Treg cells have recently been reported to inhibit some hematopoietic
precursor activity through production of TGF-β [145] . In total, these types
of observations raise the concern that a population that inhibits immune-
mediated rejection may concomitantly impair hematopoietic cell reconsti-
tution, thereby mediating apparently conflicting activities with regard to the
overall promotion of engraftment after marrow transplantation.

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Regulatory cells

CD4 + FoxP3 + T cells that comprise <10% of the peripheral CD4 compart-
ment are essential for the regulation of self-tolerance and autoimmunity
[146] . Investigators have made significant efforts to use their suppressive
capacity to control alloreactive T-cell and NK-cell responses involved in
marrow allograft rejection and GVHD [147] . Several donor and recipient
Treg cell populations can promote allogeneic marrow engraftment in MHC-
matched and MHC-mismatched recipients [148-152] . For example, ex vivo
polyclonal expanded donor and host Tregs activated with the use of micro-
spheres coated with CD3- and CD28-specific monoclonal antibodies pro-
moted engraftment of MHC-mismatched marrow in sublethally irradiated
recipients [148] . In addition, naturally occurring CD4 + CD25 + also promoted
early and long-term hematopoietic engraftment of donor progenitor cells
after co-transplantation with T-cell-deficient, MHC-mismatched marrow in
sublethally irradiated recipients [149] . As discussed above, recipient NKT
cells can interact with donor Treg cells to facilitate engraftment [81] .

In vitro -expanded recipient B6 Tregs activated against H2-mismatched
DBA/2 or B6D2-F1 APC have been evaluated for their ability to facilitate
engraftment of marrow cells from DBA/2 or third-party donors in B6 recipi-
ents [151] . The results showed that Tregs activated with DBA/2 APC facili-
tated engraftment of marrow from DBA/2 donors but not from third-party
donors. These findings are consistent with regulation by antigen-specific
Tregs. In a semi-allogeneic transplant model, the authors found that Treg