Treatment of autoimmune diseases by hemopoietic stem cell transplantation

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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 radiation on 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.


References

1. Toma JG, Akhavan M, Fernandes KJL, Barnabe-Heider F, Sadikot A, Kaplan DR, Miller FD. 2001. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol 2001; 3: 778-784.

2. Ikehara S, Good RA, Nakamura T, Sekita K, Inoue S, Maung Maung Oo, Muso E, Ogawa K, Hamashima Y. Rationale for bone marrow transplantaion in the treatment of autoimmune disease. Proc Natl Acad Sci USA 1985; 82: 2483-2487.

3. Ikehara S, Ohtsuki H, Good RA, Asamoto H, Nakamura T, Sekita K, Muso E, Tochino Y, Ida T, Kuzuya H, Imura H, Hamashima Y. Prevention of type I diabetes in nonobese diabetic mice by allogeneic bone marrow transplantation. Proc Natl Acad Sci USA 1985; 82: 7743-7747.

4. Ikehara S. Treatment of autoimmune diseases by hematopoietic stem cell transplantation. Exp Hematol 2001; 29: 661-669.

5. Baldwin JL, Strob R, Thomas ED, Mannik M. Bone marrow transplantation in patients with gold-induced marrow aplasia. Arthritis Rheum 1977; 20: 1043-1048.

6. Marmont AM. Immune ablation followed by allogeneic or autologous bone marrow transplantation. A new treatment for severe autoimmune diseases? Stem Cells 1994; 12: 125-135.

7. Burt RK. BMT for severe autoimmune diseases: An idea whose time has come. Oncology 1997; 11: 1001-1024.

8. Euler HH, Marmont AM, Bacigalupo A, Fastenrath S, Dreger P, Hoffknecht M, Zander AR, Schalke B, Hahn U, Haas R, Schmitz N. Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation. Blood 1996; 88: 3621-3625.

9. Ikehara S, Yasumizu R, Inaba M, Izui S, Hayakawa K, Sekita K, Toki J, Sugiura K, Iwai H, Nakamura T, Muso E, Hamashima Y, Good RA. Long-term observations of autoimmune-prone mice treated for autoimmune disease by allogeneic bone marrow transplantation. Proc Natl Acad Sci USA 1989; 86: 3306-3310.

10. Ishida T, M. Inaba M, Hisha H, Sugiura K, Adachi Y, Nagata N, Ogawa R, Good RA, Ikehara S. Requirement of donor-derived stromal cells in the bone marrow for successful allogeneic bone marrow transplantation. J Immunol 1994; 152: 3119-31271.

11. Hisha H, Nishino T, Kawamura M, Adachi S, Ikehara S. Successful bone marrow transplantation by bone grafts in chimeric-resistant combination. Exp Hematol 1994; 23:347-352.

12. Hashimoto F, Sugiura K, Inoue K, Ikehara S. Major histocompatibility complex restriction between hematopoietic stem cells and stromal cells in vivo. Blood 1997; 89: 49-54.

13. Takeuchi K, Inaba M, Miyashima S, Ogawa R, Ikehara S. A new strategy for treatment of autoimmune diseases in chimeric resistant MRL/lpr mice. Blood 1998; 91: 4616-4623.

14. Kushida T, Unaba M, Hisha H, Ichioka N, Esumi T, Ogawa R, Ikehara S. Intrabone marrow injection of allogeneic bone marrow cells: A powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice. Blood 2001; 97: 3292-3299.

15. Spivey WH. Intraosseous infusions. J Pediatr 1987; 111: 639-643.

16. Hagglund H, Ringden O, Agren B, Wennberg L, Remberger M, Rundquist L, Svahn B-M, Aspelin P. Intraossseous compared to intractable infusion of allogeneic bone marrow. Bone Marrow Transplant 1998; 21: 331-335.

17. Kushida T, Inaba M, Ikebukuro K, Nagahama T, Oyaizu H, Lee S, Ito T, Ichioka N, Hisha H, Sugiura K, Miyashima S, Ageyama N, Ono F, Iida H, Ogawa R, Ikehara S. A new method for bone marrow cell harvesting. Stem Cells 2000; 18: 453-456.

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