Prevention of type I diabetes in nonobese diabetic mice by allogenic bone marrow transplantation.

Abstract

An animal model [the nonobese diabetic (NOD) mouse] for type I diabetes features a striking infiltration of T cells into the pancreatic islets. This infiltration selectively destroys beta cells. Most of the T cells are Lyt-l+, but some are Lyt-2+,3+. Transfer experiments using parabiosis revealed that insulitis can be transferred within 2 weeks after parabiosis to immunoincompetent thymectomized mice. When NOD mice (6 mo old) were irradiated and reconstituted with bone marrow cells from young BALB/c nu/nu mice (<2 mo old), the NOD mice exhibited neither insulitis nor overt diabetes. Deposits of immunoglobulin in mesangial areas of the glomeruli disappeared within 3 mo after bone marrow transplantation in such irradiated allogeneic bone marrow reconstituted mice. Assays for immunological functions, including mitogen response and mixed lymphocyte reaction, revealed that both T-and B-cell functions were increased in NOD mice with overt diabetes. NOD mice reconstituted with BALB/c nu/nu bone marrow cells displayed normal T-and B-cell functions. The newly developed T cells in the allogeneic bone marrow recipients are tolerant to cells with both donor-and host-type major histocompatibility complex determinants. These results suggest that bone marrow transplantation may ultimately be developed as a component of a strategy to be employed for treatment of type I diabetes in humans.Diabetes mellitus is a heterogenous disorder, and its pathogenesis remains an enigma. It has been classified into two types (1). Type I is insulin-dependent, often juvenile-onset, nonobese, and ketosis-prone diabetes. Type II is non-insulindependent, adult-onset, obese and non-ketosis-prone diabetes. Animal models of spontaneously developing diabetes mellitus are useful for studying the pathogenesis of human diabetes mellitus and its complications. Many animal models for diabetes mellitus have been reported (2). However, most of them are models for type II diabetes. Only strain BB Wistar rats have been presented as a model for type I diabetes (3). A mouse model for type I diabetes has been sought for some time because mice are well suited for genetic and immunologic analyses.Nonobese diabetic (NOD) mice were found in 1974 by Tochino among Jcl-ICR mice with cataract and have been established recently as an inbred strain by Makino and co-workers (4). Insulitis was observed in more than 90% of both male and female NOD mice at the age of 200 days. The overt diabetic symptoms such as polyuria, polyphagia, hyperglycemia, glycosuria, and ketosis, however, appeared in 90% of the females but only 20% of the males at the age of 250 days (5). In breeding experiments with NOD and C57BL/6J mice, Makino et al. (6) found that insulitis in NOD mice is controlled by two recessive genes on independent chromosomes. Fujita et al. (7) reported that lymphocyte infiltration into the islets selectively destroys beta cells. They also found retrovirus-like particles in pancreatic beta cells of NOD mice (8).We have recently demonstrated that allogeneic bone marr...

New strategies for allogeneic BMT

“…We have previously shown, using various autoimmuneprone mice (except for MRL/lpr mice), that conventional allo BMT can be used to prevent and treat a range of autoimmune diseases. [1][2][3] 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 allogeneic BMT, since the MRL/lpr mouse itself is radiosensitive (8.5 Gy), while the abnormal hemopoietic stem cells of the MRL/lpr mouse are radioresistant (48.5 Gy); conventional BMT (8.5 Gy plus allo BMT) has a transient effect on autoimmune diseases, which regularly recur 3 months after the BMT. 4 To prevent the recurrence of autoimmune diseases in the MRL/lpr mice, we carried out BMT plus bone grafts to replace not only the hemopoietic cells but also the stromal cells with donor cells.…”

Hematopoietic stem cell transplantation for pediatric autoimmune disease: where we stand and where we need to go

“…37 Disease models of diabetes have yielded similar results. 38 As noted by others, extrapolation of animal study data to the human context is difficult as most animal studies show that transplantation can prevent rather than treat established autoimmune syndromes. 39 Ikehara's group has reported new methods for achieving infusion of essentially T cell-depleted bone marrow without technical T cell depletion.…”

Transplantation of newborn thymus plus hematopoietic stem cells can rescue supralethally irradiated mice

“…1 Using various animal models, we have found that allogeneic BMT can be used for the treatment of such diseases. [2][3][4][5][6][7][8][9] The basic theory is to replace pathogenic hematopoietic cells of hosts with normal hematopoietic stem cells (HSCs) of donors following lethal irradiation.…”