Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 91

T-cell-depleted marrow from MHC-mismatched donors, but less than one-
third of the recipients engrafted after a single 7.5 Gy TBI exposure [71] . Other
agents such as cyclophosphamide have been combined with TBI at lower
exposures to suppress resistance in murine and canine models. Although
the combination of cyclophosphamide and a single sublethal TBI expo-
sure prevented resistance in B6 mice, resistance pathways were not ablated
when the cyclophosphamide was combined with 9.0 Gy total lymphoid irra-
diation (TLI) [71] .

Efforts have been made to develop non-myeloablative conditioning regi-
mens in order to minimize toxicity while enabling engraftment of donor
cells that can medicate GVL effects. This goal has been achieved by combin-
ing non-myeloablative irradiation with several antibody- and drug-based
strategies [72,73] . In experiments using multiple exposures to TLI before
transplantation and cyclophosphamide 1 day after transplantation, most
MHC-mismatched recipients were free of GVHD and exhibited mixed chi-
merism [72] . Combinations of sublethal 3.0 Gy TBI or cyclophosphamide
together with 7.0 Gy thymic irradiation and infusion of antibodies to inhibit
T-cell-dependent resistance (anti-CD4 and CD8 mAbs) was sufficient to
enable sustained engraftment of unmanipulated marrow in MHC-mis-
matched recipients [73] .

93

In contrast to anticipated results, pre-transplant conditioning with anti-
body directed to distinct NK cell receptor subsets enhanced resistance as
measured by the higher numbers of cells needed to establish engraftment
compared to controls that were not treated with antibody [74] . Although
the mechanism for such enhanced resistance is not known, radio-resistant
effector pathways remain functional in these recipients. In mice, removal
of T-cell populations via anti-T-cell depleting reagents together with non-
lethal levels of TBI can abrogate resistance, despite the presence of a rela-
tively intact NK compartment. In many of these models, the numbers of
transplanted donor cells are sufficient to overcome NK-mediated resistance.
These results suggest that under certain transplant conditions, activated T
cells and antigen presenting cells might facilitate NK function [75,76] .

Since memory T cells have higher expression of anti-apoptotic bcl2 and
preferentially survive radiation-induced apoptosis mediated by p53 [77,78] ,
recipients that have been pre-sensitized to donor alloantigens require more
intensive pre-transplant conditioning to prevent rejection. Lethal TBI alone
is insufficient to block resistance in models even when antibody against
donor cells cannot be detected [37,40,42,51,59,79] . In contrast, following
six transfusions in pre-sensitized dogs, treatment with anti-T-cell depleting
agents before TBI overcame resistance [40] .

Pre-transplant conditioning regimens can also alter the balance of recipient
T cell and NK populations, thereby altering the host response to allografts.
Engraftment of MHC-mismatched marrow could be established when
treatment with antithymocyte serum was combined with hyper-fraction-
ated TLI (e.g., 17 exposures, 2.4 Gy per exposure) but not with a single 8.0 Gy
TBI exposure [80] . Recipients conditioned with antithymocyte serum and
fractionated TLI had increased numbers of NKT cells that expanded donor
Treg populations through an IL-4-dependent pathway, thereby enhancing
the regulation of alloimmune responses after transplantation [81] .