Treatment of autoimmune diseases by hemopoietic stem cell transplantation
S. Ikehara, First Department of Pathology, Transplantation Center,
Regeneration Research
Center for Intractable Diseases, Kansai Medical University, Osaka
Klinik
& Forschung 2002; 8(2):49-50
Stem
cells
have recently been isolated from various organs and tissues, and have been shown
to have far more plasticity than expected.For example, it has very recently been shown that multipotent adult stem
cells isolated from the dermas of mammalian skin can proliferate and
differentiate into neurons, glia, smooth muscle cells, and adipocytes in vitro1.
We
have previously shown using various autoimmune-prone mice that conventional
allogeneic bone marrow transplantation (allo BMT) can be used to prevent and
treat a range of autoimmune diseases2-4. These findings have recently been confirmed
even in humans5-7. However, in humans, the success rate of BMT
across major histocompatibility complex (MHC) barriers is lowered by
graft-versus-host disease (GvHD), graft rejection, and incomplete T-cell
recovery.Therefore, autologous BMT
(auto BMT) or peripheral blood stem cell transplantation (auto PBSCT) is the
preferred treatment for autoimmune diseases.There
have, however, been reports on the rapid recurrence or persistence of autoimmune
diseases after auto BMT or auto PBSCT8.Therefore, it is important to establish a
safe new method for allo BMT.
We
have found that the MRL/lpr mouse, an animal model for autoimmune diseases, is a
suitable model for establishing a safe new strategy for allo BMT, since the MRL/lpr
mouse itself is radio-sensitive (<8.5Gy), while the abnormal hemopoietic stem
cells of the MRL/lpr mouse are radio-resistant (>8.5Gy); conventional BMT
(8.5Gy plus allo BMT) has a transient effect on autoimmune diseases, which recur
3 months after the BMT9.However, we have found
that BMT plus bone grafts (to recruit donor stromal cells) completely prevents
the recurrence of autoimmune diseases in MRL/lpr mice10;
donor-derived stromal cells (including mesenchymal stem cells) seem to play a
crucial role in successful allo BMT10,11, since there is
an MHC restriction between hemopoietic stem cells (HSCs) and stromal cells12. We have, however, found that the combination of BMT plus bone grafts
has no effect on the treatment of autoimmune diseases in MRL/lpr mice13, since MRL/lpr mice become more radiosensitive after the onset of lupus
nephritis due to the development of uremic enterocolitis.To reduce the cytotoxic effect of radiationon the intestine, we carried out fractionated irradiation and devised a
new strategy. We injected allogeneic whole BMCs (including a small number
(<3%) of T cells, HSCs, and stromal cells) of donors directly into the
intra-bone marrow (IBM) of recipients (IBM-BMT) so that donor-derived
hemopoietic cells including stromal cells could effectively accumulate in the
bone marrow. All the MRL/lpr mice survived more than one year (>60 weeks
after birth) without the recurrence of autoimmune diseases, and immunological
functions were completely restored even when the radiation dose was reduced to 5
Gy x 214.These findings suggest that IBM-BMT can be used to treat intractable
autoimmune diseases under reduced radiation doses without using any
immunosuppressants.
IBM-BMT
seems to be the best strategy for allo BMT: i) no GvHD develops even if T cells
are not depleted from the bone marrow; ii) no graft failure occurs even if the
dose of radiation as the conditioning for BMT is reduced to 5Gy x 2; iii)
hemopoietic recovery is rapid; and iv) the restoration of T cell functions is
complete even in donor-recipient combinations across the MHC barriers.We believe that this “IBM-BMT” is applicable to humans, since
intraosseous (i.o.) infusion (IBM-injection) is an established method for
administering fluids, drugs, and blood to critically ill patients, particularly
infants15.Indeed, Hagglund et al. have recently compared the effectiveness of i.o.
infusion with that of i.v. infusion in human allo BMT16; they have
concluded that allo BMT can be safely performed by i.o. infusion, but the
incidences of acute and chronic GvHD, transplantation-related mortality, and
survival rates are similar.However,
they aspirated the donor BMCs from the iliac bones and infused these BMCs into
the iliac bones of the recipients.
Using
cynomolgus monkeys, we have just established a new method (“Perfusion Method”)
for collecting BMCs from the long bones (femur, humerus, etc.) without
peripheral blood contamination17. This method has various advantages: i) no GvHD develops even in
cynomolgus monkeys, since the percentage of T cells in the BMCs thus collected
is less than 3%, ii) a large number of BMCs can be collected quickly and safely,
and iii) the BMCs thus collected contain stromal cells including mesenchymal
stem cells. We therefore believe that this method (IBM-BMT in conjunction with
“Perfusion Method”) will become a powerful new strategy for not only allo
BMT but also organ transplantation in conjunction with BMT. Furthermore, this
method would become a valuable strategy for regeneration therapy of injured
organs and tissues (myocardial infarction, cerebral infarction, Alzheimer’s
disease, etc.), since IBM-BMT can efficiently reconstitute the recipient with
both donor-derived hemopoietic stem cells and mesenchymal stem cells.
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