A More Persistent Tolerance to Islet Allografts Through Bone Marrow
Transplantation in Minimal Nonmyleoablative Conditioning Therapy
B.-W. Lee, J.I. Lee, S.H. Oh, Y.R. Ahn, H.Y. Chae, M.S. Lee, M.K. Lee, and K.W. Kim
ABSTRACT
Introduction. Islet transplantation is a therapeutic approach to prevent diabetes compli-
cations. However, the side effects of the required lifelong immunosuppressive regimens to
prevent graft rejection restrict the impact of type 1 diabetes. One strategy to overcome
these limitations is tolerance induction and graft acceptance through hematopoietic
chimerism. In this study we investigated whether tolerance to major histocompability
complex (MHC) and minor-disparate islet allografts could be induced by minimal
nonmyeloablative conditioning and whether more persistent donor-specific islet allografts
were accepted if the grafts were implanted with simultaneous bone marrow cells.
Methods. The donor and recipient mice were BALB/c(H-2
b
) and C57BL/6(H-2
d
), respectively.
In group 1 streptozotocin-induced diabetic C57BL/6(H-2
d
) mice received only 500 islets of
BALB/c(H-2
b
). Group 2 recipients conditioned with antilymphocyte serum, 100 cGy total body
irradiation and cyclophosphamide were given islet cells of BALB/c(H-2
b
), but group 3 were
simultaneously given 30 10
6
BALB/c(H-2
b
) mice BMCs and islet cells similar to group 2.
Results. We obtained 5% to 6% allogeneic donor chimerism and 60% graft survival at
80 days after islet transplantation in group 3. We observed lymphocyte infiltration around
the islet without destruction of endocrine cells and the presence of strong insulin/glucagon-
stained cells in group 3.
Conclusion. This minimal nonmyeloablative conditioning therapy induced donor chi-
merism and immune tolerance between MHC- and minor-disparate (BALB/c¡C57BL/6)
mice and long-term islet graft survival was obtained through cotransplantation of bone
marrow cells.
I
SLET TRANSPLANTATION (IT) is a therapeutic op-
tion to prevent diabetes complications for insulin-
deficient patients state. However, the side effects of lifelong
immunosuppressive regimens to prevent graft rejection
restrict this treatment for type I diabetes. One strategy to
overcome these limitations is tolerance induction and graft
acceptance through hematopoietic chimerism.
1
Although
several tolerance approaches
1–4
have been tried, the role of
bone marrow cells (BMCs) in conditioning experiments has
not been fully elucidated. In this study, we investigated
whether tolerance to major histocompability complex
(MHC)- and minor-disparate islet allografts was induced by
a minimal nonmyeloablative conditioning regimen and
whether more persistent acceptance of donor-specific islet
allografts was obtained if they were implanted with simul-
taneous BMC transplantation.
MATERIALS AND METHODS
Animals
Donor and recipient mice purchased from the CriBgi of Cheles
River Technology were 12- to 13-week old inbred male BALB/c
(H-2
b
) and 10- to 11-week-old inbred male C57BL/6(H-2
d
), respec-
tively.
From the Division of Endocrinology and Metabolism (B.-W. L.,
S.-H. O., M.-S. L., M.-K. L., K.-W. K.), Department of Medicine,
Samsung Medical Center, Sungkyunkwan University School of
Medicine and Samsung Biomedical Research Institute (J.-I. L.,
Y.-R. A., H.-Y. C.), Seoul, Korea.
Address reprint requests to Kwang-Won Kim, Division of
Endocrinology and Metabolism, Department of Medicine, Sam-
sung Medical Center, Sungkyunkwan University School of Med-
icine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea.
E-mail: kwwkim@smc.samsung.co.kr
0041-1345/05/$–see front matter © 2005 by Elsevier Inc. All rights reserved.
doi:10.1016/j.transproceed.2005.03.044 360 Park Avenue South, New York, NY 10010-1710
2266 Transplantation Proceedings, 37, 2266 –2269 (2005)