Biology Reference
In-Depth Information
lineage-specific markers, and these cells represent approximately 1 in 1000
marrow cells (reviewed in reference
[102]
).
Experiments with a congenic strain combination having a marker that can
be used to distinguish donor and recipient cells showed that 20 to 40 donor
cells of the HSC-enriched population were required to rescue 50% of recipi-
ents from lethal irradiation, and 100 cells were sufficient to rescue nearly all
recipients
[102]
. Comparable experiments with whole marrow showed that
approximately 4 × 10
4
cells were required to rescue 50% of the recipients,
and 2 × 10
5
cells were sufficient to rescue nearly all recipients.
Results were distinctly different in allogeneic recipients. In an MHC-
matched strain combination with mismatching for multiple minor anti-
gens where rejection is mediated by recipient T cells, 500 donor cells of the
isolated HSC-enriched population rescued only 20% of the recipients, and
1000 cells rescued most recipients. Thus, a 10-fold increase in the number
of HSC-enriched cells could overcome the resistance barrier in this strain
combination compared to the congenic strain combination. As few as 1 ×
10
6
whole marrow cells containing an estimated 500 cells with the HSC cell
surface phenotype rescued all lethally irradiated recipients, suggesting that
cells lacking the HSC phenotype are able to facilitate engraftment under
these conditions. Results were similar in experiments with parental donors
and F1 recipients where rejection was mediated by recipient NK cells.
100
In a strain combination with mismatching for both major and minor his-
tocompatibility antigens where donor cells could be recognized both by
recipient T cells and NK cells, 3000 cells of the isolated HSC-enriched popu-
lation rescued approximately 60% of the recipients, and 6000 cells rescued
all recipients. Thus, a 30- to 50-fold increase in the number of HSC-enriched
cells could overcome the resistance barrier in this strain combination com-
pared to the congenic strain combination. In this strain combination, as
little as 1 × 10
6
whole marrow cells containing an estimated 500 cells with
the HSC phenotype could rescue nearly all recipients, again suggesting
that cells lacking the HSC cell surface phenotype are also able to facilitate
engraftment.
The mechanism by which HSC-enriched cell populations facilitate engraft-
ment in allogeneic recipients appears to be related to an inhibitory effect on
recipient T cells that recognize recipient alloantigens
[103]
. After transplan-
tation of HSC-enriched donor cells into sublethally irradiated allogeneic
recipients, stimulated spleen cells from engrafted recipients could generate
cytotoxic T cells that recognize third-party alloantigens but not donor-spe-
cific alloantigens. Stimulated spleen cells from sublethally irradiated mice
that were not given donor cells could generate cytotoxic T cells that rec-
ognized alloantigens of both strains. In mixed lymphocyte cultures, HSC-
enriched cells inhibited the development of cytotoxic T cells that recognize
alloantigens of the HSC strain and had no effect on the development of
cytotoxic T cells that recognize alloantigens of other strains. HSC-depleted
cells did not inhibit the development of cytotoxic T cells that recognize allo-
antigens of the HSC strain.
In mixed lymphocyte cultures, human CD34
+
cells have a similar ability to
inhibit specific cytotoxic responses against alloantigens expressed by the
Search WWH ::
Custom Search