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interleukin 2 receptor system in type 1 diabetes
Diabetes Rcwurch and Clinical Practice, 7 ( 1989) S67472
S67
Elsevier
DIABET
K0042
Interleukin 2/interleukin 2 receptor system in type 1 diabetes Nobuo
Hatamori,
Koichi
Yokono,
Masao
Second Department of’lntrrnal Medicine and ‘Department
Nagata,
Kunihiro
Doi
and
Shigeaki
Baba
qf Internal Medicine. Metabolic LX/. Kohe Unirersify School of Medicine. Kobe 650, Japun
Key wordx. Type
1 diabetes; Interleukin
2: Interleukin
2 receptor
Introduction There is increasing evidence that cellular immune abnormalities are involved in the pathogenesis of type 1 diabetes mellitus. The non-obese diabetic (NOD) mouse, a model of human type 1 diabetes, develops mononuclear cell infiltration of its pancreatic islets (insulitis), leading to /3 cell destruction and overt diabetes [l]. In recent studies, most of the islet-infiltrating cells in the NOD mouse were determined to be T cells by immunohistochemistry [2] and electron microscopy [3]. Furthermore, neonatal thymectomy [4], the administration of anti-thymocyte serum [5], or the transfer of the nude gene [6] has prevented insulitis and the development of diabetes in this animal model. These findings strongly suggest that T lymphocyte-mediated autoimmunity underlies the autoimmune phenomenon in NOD mice. Interleukin 2 (IL-2) is produced by antigen- or mitogen-activated T lymphocytes and plays a central role in the development of the immune re__-. Address partment
for correspondence: of Internal
Medicine,
Dr. N. Hatamori, Kobe University Chuo-ku,
Second
De-
School of Med-
icine, Kusunoki-cho.
7-chome,
Kobe 650, Japan.
016%87271X9/$03.50
ii;: 1989 Elsevier Science Publishers
sponse. As are other classic peptide hormones, IL-2 is thought to act on T cells through its receptor. IL-2 and its surface receptor (IL-2R) have been shown to be essential components in the growth and proliferation of the effector cells of immunity. Thus. since IL-2 plays an important role in cellmediated immunity, it is assumed that an abnormality in the IL-2/IL-2R system participates in the T cell dysfunction of NOD mice. In this paper, to clarify the pathogenic significance of the IL-2/ IL-2R abnormality of type 1 diabetes, we have tried to compile the available references, including our own data.
IL-2/IL-2R
system (Fig. 1)
IL-2 is a polypeptide hormone (15,000 daltons) produced by both helper and suppressor T cells that governs the clonal expansion and reactivity of T cells [7-91. The mechanism of action of IL-2 involves its binding to IL-2R on the surface of responsive cells [ 10,111. As with the receptors for epidermal growth factor, interferon and peptide hormones. there exist two classes of IL-2R with high (H-IL-2R) and low affinity (L-IL-2R). Their Kd val-
B.V. (Biomedical
Division)
S68 Interleukin
2 Receptor
nuclear cells bear less than 2% IL-2R as detected by
(IL-2R)
anti-Tat antibody [12,18]. By comparison, every recently activated, proliferating T cell and some recently activated B cells bear H-IL-2R [19-221. HIL-2R are only transiently expressed upon lymphocytes during
the antigen-
or mitogen-driven
prolif-
erative burst. Furthermore, only H-IL-2R are internalized and mediate the biological action of IL-2, although
L-IL-2R
are also expressed
on the cell sur-
face [23,24].
IL-2 production (Table 1)
/ High-affiruty
IL-2R
Low-affmlty
Fig. 1. The two classes of interleukin
2 surface
IL-2R
Defects in IL-2 production have been reported among mitogen-stimulated lymphocytes from human type 1 diabetes [25], NOD mice [26], and BB rats [27]. Moreover, low levels of IL-2 production have been found among the lymphocytes of patients under good control as well as those under poor control, and this defect was independent of the duration of disease. These data suggest that decreased IL-2 synthesis is specific for type 1 diabetes, and not explainable solely as a consequence of poor metabolic control; thus, it might be involved in the pathogenesis of the disease. In addition, similar defects have been reported in human autoimmune diseases, such as rheumatoid arthritis [28] and systemic lupus erythematosus (SLE) [29]. We have also examined the IL-2 production of mitogen-activated spleen
receptor.
ues were approximately 10 pM and 10 nM respectively, while the number of L-IL-2R was 5-10 times greater than that of H-IL-2R [12]. A cross-linking study using radiolabeled IL-2 has revealed that a 70-kDa membrane glyoprotein (p70), together with a 55 kDa Tat antigen, constitutes H-IL-2R, and that the Tat antigen alone constitutes L-IL-2R [13151. The Tat antigen is a protein detected by antiTat monoclonal antibody, produced by Uchiyama et al., and is considered to be IL-2R itself or a closely related structure [16]. Robb and Green observed that anti-Tat antibody bound to both receptors [ 171, and others that resting populations of monoTABLE
1
IL-2/IL-2R
ABNORMALITIES
IN TYPE
I DIABETES
Mitogen-activated
MELLITUS
lymphocytes
DESCRIBED
..~_
___
IL-2 production
Proliferative
Decreased
Decreased
IN THE LITERATURE
IL-ZR-positive
activated
lymphocytes
(antigen-activated)
response
_ Human
type
I diabetes
NOD mice
Decreased
[25]
[26]
Decreased
[3 I]
[30]
Increased Peripheral
blood [33,34]
- Pancreatic
islets [35]
Increased Pancreatic
islets [36]
.- CTL derived BB rats
Decreased
[27]
ND
- Pancreatic ND, not determined.
from islet-infiltrating
Increased islets [37]
cells [38]
S69 lymphocytes
from NOD
valin A (con A) stimulation
of lo-week-old
mice, IL-2 production dropped ever, stimulation of 3-week-old phytohemagglutinin
CTL as they are antigen-specific
mice [30]. After concana-
(PHA)
NOD
significantly. Howmice with con A or
had no significant
fect. The fact that defects of IL-2 production served in several autoimmune disorders
de-
are oband can
precede the diseases suggests that IL-2 deficiency
is
somehow related to pathogenesis. Since IL-2 plays a central role in normal immunoregulation, IL-2 deficiency might contribute in some unknown way to an immunoregulatory imbalance and thus to the development of an autoimmune reaction.
Expression of IL-2R (Table 1) Impaired responsiveness to exogenous IL-2 has also been reported for mitogen-stimulated peripheral lymphocytes from patients with type 1 diabetes [3 l] and SLE [32]. Moreover, Scatchard analysis using radiolabeled IL-2 revealed impaired expression of H-IL-2R on mitogen-stimulated lymphocytes from patients with SLE 1321. Conversely, several studies have reported that IL-2R-positive activated lymphocytes were unusually abundant in the peripheral blood of patients with recent-onset type 1 diabetes [33,34], and had infiltrated into the pancreatic islets of human [35] and animal type 1 diabetics [36,37]. Therefore, in addition to IL-2 production, it is very important to investigate the expression of IL-2R on activated lymphocytes. We have examined the expression of IL-2R on antigen- and mitogen-stimulated lymphocytes from NOD mice [30]. Recently, we have successfully isolated proliferating mononuclear cells from islets of NOD mice by culturing them with recombinant IL-2. These islet-derived cells expressing Thyl.2 and Lyt2 phenotypes kill NOD islet cells directly [38]. Furthermore, by evaluating the ability of these cells to destroy islets from various strains of mice, we have determined these islet-derived cells to be cytotoxic T lymphocytes (CTL) which recognize islet-cell antigens of major histocompatibility complex (MHC) class I. We have investigated the expression of IL-2R on these
cytes. As a first step, splenic NOD
and control
activated
lymphocytes
BALB/c
lympho-
from female
mice were stimulated
with con A (con A blasts) and PHA. We then measured their responsiveness to exogenous IL-2. The proliferative nificantly
response
of each blast to IL-2 was sig-
lower in NOD mice than in BALB/c mice.
To find the reason the expression
for this defect, we investigated
of IL-2R
on con
A blasts
with
Scatchard analysis and a cross-linking study. The number of H-IL-2R. the mediator of the biological activity of IL-2, was significantly smaller in NOD mice, whereas there was no significant difference in the numer of L-IL-2R. Chemical cross-linking of ‘251-IL-2 bound to H-IL-2R of con A blasts labels both p70 and Tat proteins. The radioactivities of these bands were quantitatively lower in con A blasts from NOD mice. On the other hand, the specific binding of rz51-IL-2 to CTL was significantly higher than that of L3T4+ and Lyt2+ spleen T lymphocytes cultured with IL-2 (no antigen stimulation). IL-2 binding to CTL was approximately the same as that of CTLL-2 cells (a murine IL-2-dependent T cell line). These data suggest that IL-2R on antigen-specific effector cells were fully expressed, although the expression of IL-2R on mitogen (non-specific)-activated spleen T lymphocytes was impaired.
Immune intervention trials (Table 2) Interleukin 2 The effect of IL-2 administration has been examined [39]. Treatment of BB rats with recombinant IL-2 enhanced the development of spontaneous diabetes in these animals. A dose of 20 pg/kg body weight was administered twice daily for 80 days starting at 42 days of age. The incidence of diabetes was doubled after IL-2 administration (53% vs. 23%) and the period of onset was found to be accelerated. These data indicate that IL-2 has a regulatory effect on spontaneous organ-specific autoimmmunity.
s70 TABLE
2
IMMUNE
INTERVENTION
Immunomodulator
TRIALS
DESCRIBED
EtFxt on diabetes Human
Interleukin Monoclonal
2 anti-IL-?R
IN THE LITERATIJRE
development
type I diabetes
ND
ND
ND
Suppression
Cyclosporine
Suppression
OK-432
ND
[43]
BB rats
NOD mice
Enhancement
[39]
[40]
Suppression
[41]
Suppression
[43]
Suppression
[44.45]
Suppression
[46]
ND
ND. not determined
Morzoclonul anti-IL-JR untiho~~~ Treatment with monoclonal anti-IL-2R antibody. which recognizes the 55-kDa subunit of H-IL-2R, has been reported to suppress the development of diabetes in NOD mice [40] and BB rats [41]. NOD mice were injected intraperitoneally daily beginning at 5 weeks of age (before insulitis) with 5 pg of purified IgM anti-IL-2R monoclonal antibody (M7/20). Treatment with M7j20 for 5 weeks reduced the autoimmune insulitis in NOD mice [40]. The shortterm treatment with anti-IL-2R monoclonal antibody ART-l 8 (1 .O mg/kg b.w.) in combination with a subtherapeutic dose of cyclosporine (1.5 mgikg b.w.) for 10 days has also been reported to be successful in the prevention of the autoimmune disease in newly diagnosed diabetic BB rats [41]. These studies suggest the importance of IL-2R-positive activated lymphocytes and macrophages in the pathogenesis of autoimmunity. Cyclosporine Cyclosporine is a fungal metabolite which has potent immunosuppressive effects without significant myelotoxicity. In experimental animals, the administration of cyclosporine has been shown to remarkably prolong the survival of MHC-incompatible organ allografts. Cyclosporine has been found to suppress the production of IL-2 and to block IL-2R on activated lymphocytes. Stiller et al. have reported the effects of cyclosporine in type 1 diabetes of recent onset [42]. Forty-one patients with type 1 diabetes were treated with cyclosporine (10 mgikg
b.w.) for 2-12 months. Of 30 patients treated within 6 weeks of diagnosis, 16 became insulin-independent with concentrations of plasma C-peptide in the normal range and decreasing titers of islet cell antibodies. Of 11 patients who entered the study 8-44 weeks after diagnosis, two achieved this stage. Moreover, prevention of diabetes by cyclosporine has been demonstrated in NOD mice [43] and BB rats [44,45]. NOD mice aged 30-60 days were treated orally with cyclosporine (2.5-25 mg/kg b.w.) every 2 days until 160 days of age. These cyclosporinetreated NOD mice showed neither insulitis nor the development of diabetes. Pretreatment with cyclosporine of diabetes-prone BB rats at lo-day intervals before age 70 days also significantly reduced the frequency and delayed the onset of diabetes [45]. OK-432 OK-432, a preparation of group A streptococcus pyrogens, has preventive effects on type 1 diabetes in NOD mice [46]. Two CU (clinical unit) of OK-432 were given intraperitoneally every week from 4 to 24 weeks of age. The administration of OK-432 suppressed the development of diabetes. Histological examination showed that in the OK-432-treated NOD mice, 98% of the islets were intact or mildly infiltrated with mononuclear cells. OK-432 has been reported to enhance interferon and IL-2 production and thus possibly normalizes lymphokine levels and suppressor activity in NOD mice.
s71 6 Makino.
Conclusion
S., Harada,
(1986) Absence
All these reports
strongly
nude mice with NOD
suggest that the dysfunc-
tion of IL-2 and its surface receptor tant role in the pathogenesis
though the precise mechanisms abnormality of the IL-2/IL-2R solved in type 1 diabetes,
Al-
responsible for the system remain un-
it is speculated
and
genetic
Y. and
overt
Hayashi
diabetes
background.
Y.
in athymic
Exp. Anim.
35.
495-498.
plays an impor-
of type 1 diabetes.
M.. Kishimoto.
of insulitis
that regu-
latory T cells demonstrating defective IL-2 production and H-IL-2R expression are capable of neither expanding clonally nor maturing functionally, allowing the generation of islet-specific autoreactive cells. Therefore, studies of the IL-2/IL-2R system, especially of the mechanism involved in the abnormal expression of IL-2R, have not only clarified the pathogenesis of type 1 diabetes, but may also have provided new reagents useful in the prevention and treatment of type 1 diabetes.
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S67
Elsevier
DIABET
K0042
Interleukin 2/interleukin 2 receptor system in type 1 diabetes Nobuo
Hatamori,
Koichi
Yokono,
Masao
Second Department of’lntrrnal Medicine and ‘Department
Nagata,
Kunihiro
Doi
and
Shigeaki
Baba
qf Internal Medicine. Metabolic LX/. Kohe Unirersify School of Medicine. Kobe 650, Japun
Key wordx. Type
1 diabetes; Interleukin
2: Interleukin
2 receptor
Introduction There is increasing evidence that cellular immune abnormalities are involved in the pathogenesis of type 1 diabetes mellitus. The non-obese diabetic (NOD) mouse, a model of human type 1 diabetes, develops mononuclear cell infiltration of its pancreatic islets (insulitis), leading to /3 cell destruction and overt diabetes [l]. In recent studies, most of the islet-infiltrating cells in the NOD mouse were determined to be T cells by immunohistochemistry [2] and electron microscopy [3]. Furthermore, neonatal thymectomy [4], the administration of anti-thymocyte serum [5], or the transfer of the nude gene [6] has prevented insulitis and the development of diabetes in this animal model. These findings strongly suggest that T lymphocyte-mediated autoimmunity underlies the autoimmune phenomenon in NOD mice. Interleukin 2 (IL-2) is produced by antigen- or mitogen-activated T lymphocytes and plays a central role in the development of the immune re__-. Address partment
for correspondence: of Internal
Medicine,
Dr. N. Hatamori, Kobe University Chuo-ku,
Second
De-
School of Med-
icine, Kusunoki-cho.
7-chome,
Kobe 650, Japan.
016%87271X9/$03.50
ii;: 1989 Elsevier Science Publishers
sponse. As are other classic peptide hormones, IL-2 is thought to act on T cells through its receptor. IL-2 and its surface receptor (IL-2R) have been shown to be essential components in the growth and proliferation of the effector cells of immunity. Thus. since IL-2 plays an important role in cellmediated immunity, it is assumed that an abnormality in the IL-2/IL-2R system participates in the T cell dysfunction of NOD mice. In this paper, to clarify the pathogenic significance of the IL-2/ IL-2R abnormality of type 1 diabetes, we have tried to compile the available references, including our own data.
IL-2/IL-2R
system (Fig. 1)
IL-2 is a polypeptide hormone (15,000 daltons) produced by both helper and suppressor T cells that governs the clonal expansion and reactivity of T cells [7-91. The mechanism of action of IL-2 involves its binding to IL-2R on the surface of responsive cells [ 10,111. As with the receptors for epidermal growth factor, interferon and peptide hormones. there exist two classes of IL-2R with high (H-IL-2R) and low affinity (L-IL-2R). Their Kd val-
B.V. (Biomedical
Division)
S68 Interleukin
2 Receptor
nuclear cells bear less than 2% IL-2R as detected by
(IL-2R)
anti-Tat antibody [12,18]. By comparison, every recently activated, proliferating T cell and some recently activated B cells bear H-IL-2R [19-221. HIL-2R are only transiently expressed upon lymphocytes during
the antigen-
or mitogen-driven
prolif-
erative burst. Furthermore, only H-IL-2R are internalized and mediate the biological action of IL-2, although
L-IL-2R
are also expressed
on the cell sur-
face [23,24].
IL-2 production (Table 1)
/ High-affiruty
IL-2R
Low-affmlty
Fig. 1. The two classes of interleukin
2 surface
IL-2R
Defects in IL-2 production have been reported among mitogen-stimulated lymphocytes from human type 1 diabetes [25], NOD mice [26], and BB rats [27]. Moreover, low levels of IL-2 production have been found among the lymphocytes of patients under good control as well as those under poor control, and this defect was independent of the duration of disease. These data suggest that decreased IL-2 synthesis is specific for type 1 diabetes, and not explainable solely as a consequence of poor metabolic control; thus, it might be involved in the pathogenesis of the disease. In addition, similar defects have been reported in human autoimmune diseases, such as rheumatoid arthritis [28] and systemic lupus erythematosus (SLE) [29]. We have also examined the IL-2 production of mitogen-activated spleen
receptor.
ues were approximately 10 pM and 10 nM respectively, while the number of L-IL-2R was 5-10 times greater than that of H-IL-2R [12]. A cross-linking study using radiolabeled IL-2 has revealed that a 70-kDa membrane glyoprotein (p70), together with a 55 kDa Tat antigen, constitutes H-IL-2R, and that the Tat antigen alone constitutes L-IL-2R [13151. The Tat antigen is a protein detected by antiTat monoclonal antibody, produced by Uchiyama et al., and is considered to be IL-2R itself or a closely related structure [16]. Robb and Green observed that anti-Tat antibody bound to both receptors [ 171, and others that resting populations of monoTABLE
1
IL-2/IL-2R
ABNORMALITIES
IN TYPE
I DIABETES
Mitogen-activated
MELLITUS
lymphocytes
DESCRIBED
..~_
___
IL-2 production
Proliferative
Decreased
Decreased
IN THE LITERATURE
IL-ZR-positive
activated
lymphocytes
(antigen-activated)
response
_ Human
type
I diabetes
NOD mice
Decreased
[25]
[26]
Decreased
[3 I]
[30]
Increased Peripheral
blood [33,34]
- Pancreatic
islets [35]
Increased Pancreatic
islets [36]
.- CTL derived BB rats
Decreased
[27]
ND
- Pancreatic ND, not determined.
from islet-infiltrating
Increased islets [37]
cells [38]
S69 lymphocytes
from NOD
valin A (con A) stimulation
of lo-week-old
mice, IL-2 production dropped ever, stimulation of 3-week-old phytohemagglutinin
CTL as they are antigen-specific
mice [30]. After concana-
(PHA)
NOD
significantly. Howmice with con A or
had no significant
fect. The fact that defects of IL-2 production served in several autoimmune disorders
de-
are oband can
precede the diseases suggests that IL-2 deficiency
is
somehow related to pathogenesis. Since IL-2 plays a central role in normal immunoregulation, IL-2 deficiency might contribute in some unknown way to an immunoregulatory imbalance and thus to the development of an autoimmune reaction.
Expression of IL-2R (Table 1) Impaired responsiveness to exogenous IL-2 has also been reported for mitogen-stimulated peripheral lymphocytes from patients with type 1 diabetes [3 l] and SLE [32]. Moreover, Scatchard analysis using radiolabeled IL-2 revealed impaired expression of H-IL-2R on mitogen-stimulated lymphocytes from patients with SLE 1321. Conversely, several studies have reported that IL-2R-positive activated lymphocytes were unusually abundant in the peripheral blood of patients with recent-onset type 1 diabetes [33,34], and had infiltrated into the pancreatic islets of human [35] and animal type 1 diabetics [36,37]. Therefore, in addition to IL-2 production, it is very important to investigate the expression of IL-2R on activated lymphocytes. We have examined the expression of IL-2R on antigen- and mitogen-stimulated lymphocytes from NOD mice [30]. Recently, we have successfully isolated proliferating mononuclear cells from islets of NOD mice by culturing them with recombinant IL-2. These islet-derived cells expressing Thyl.2 and Lyt2 phenotypes kill NOD islet cells directly [38]. Furthermore, by evaluating the ability of these cells to destroy islets from various strains of mice, we have determined these islet-derived cells to be cytotoxic T lymphocytes (CTL) which recognize islet-cell antigens of major histocompatibility complex (MHC) class I. We have investigated the expression of IL-2R on these
cytes. As a first step, splenic NOD
and control
activated
lymphocytes
BALB/c
lympho-
from female
mice were stimulated
with con A (con A blasts) and PHA. We then measured their responsiveness to exogenous IL-2. The proliferative nificantly
response
of each blast to IL-2 was sig-
lower in NOD mice than in BALB/c mice.
To find the reason the expression
for this defect, we investigated
of IL-2R
on con
A blasts
with
Scatchard analysis and a cross-linking study. The number of H-IL-2R. the mediator of the biological activity of IL-2, was significantly smaller in NOD mice, whereas there was no significant difference in the numer of L-IL-2R. Chemical cross-linking of ‘251-IL-2 bound to H-IL-2R of con A blasts labels both p70 and Tat proteins. The radioactivities of these bands were quantitatively lower in con A blasts from NOD mice. On the other hand, the specific binding of rz51-IL-2 to CTL was significantly higher than that of L3T4+ and Lyt2+ spleen T lymphocytes cultured with IL-2 (no antigen stimulation). IL-2 binding to CTL was approximately the same as that of CTLL-2 cells (a murine IL-2-dependent T cell line). These data suggest that IL-2R on antigen-specific effector cells were fully expressed, although the expression of IL-2R on mitogen (non-specific)-activated spleen T lymphocytes was impaired.
Immune intervention trials (Table 2) Interleukin 2 The effect of IL-2 administration has been examined [39]. Treatment of BB rats with recombinant IL-2 enhanced the development of spontaneous diabetes in these animals. A dose of 20 pg/kg body weight was administered twice daily for 80 days starting at 42 days of age. The incidence of diabetes was doubled after IL-2 administration (53% vs. 23%) and the period of onset was found to be accelerated. These data indicate that IL-2 has a regulatory effect on spontaneous organ-specific autoimmmunity.
s70 TABLE
2
IMMUNE
INTERVENTION
Immunomodulator
TRIALS
DESCRIBED
EtFxt on diabetes Human
Interleukin Monoclonal
2 anti-IL-?R
IN THE LITERATIJRE
development
type I diabetes
ND
ND
ND
Suppression
Cyclosporine
Suppression
OK-432
ND
[43]
BB rats
NOD mice
Enhancement
[39]
[40]
Suppression
[41]
Suppression
[43]
Suppression
[44.45]
Suppression
[46]
ND
ND. not determined
Morzoclonul anti-IL-JR untiho~~~ Treatment with monoclonal anti-IL-2R antibody. which recognizes the 55-kDa subunit of H-IL-2R, has been reported to suppress the development of diabetes in NOD mice [40] and BB rats [41]. NOD mice were injected intraperitoneally daily beginning at 5 weeks of age (before insulitis) with 5 pg of purified IgM anti-IL-2R monoclonal antibody (M7/20). Treatment with M7j20 for 5 weeks reduced the autoimmune insulitis in NOD mice [40]. The shortterm treatment with anti-IL-2R monoclonal antibody ART-l 8 (1 .O mg/kg b.w.) in combination with a subtherapeutic dose of cyclosporine (1.5 mgikg b.w.) for 10 days has also been reported to be successful in the prevention of the autoimmune disease in newly diagnosed diabetic BB rats [41]. These studies suggest the importance of IL-2R-positive activated lymphocytes and macrophages in the pathogenesis of autoimmunity. Cyclosporine Cyclosporine is a fungal metabolite which has potent immunosuppressive effects without significant myelotoxicity. In experimental animals, the administration of cyclosporine has been shown to remarkably prolong the survival of MHC-incompatible organ allografts. Cyclosporine has been found to suppress the production of IL-2 and to block IL-2R on activated lymphocytes. Stiller et al. have reported the effects of cyclosporine in type 1 diabetes of recent onset [42]. Forty-one patients with type 1 diabetes were treated with cyclosporine (10 mgikg
b.w.) for 2-12 months. Of 30 patients treated within 6 weeks of diagnosis, 16 became insulin-independent with concentrations of plasma C-peptide in the normal range and decreasing titers of islet cell antibodies. Of 11 patients who entered the study 8-44 weeks after diagnosis, two achieved this stage. Moreover, prevention of diabetes by cyclosporine has been demonstrated in NOD mice [43] and BB rats [44,45]. NOD mice aged 30-60 days were treated orally with cyclosporine (2.5-25 mg/kg b.w.) every 2 days until 160 days of age. These cyclosporinetreated NOD mice showed neither insulitis nor the development of diabetes. Pretreatment with cyclosporine of diabetes-prone BB rats at lo-day intervals before age 70 days also significantly reduced the frequency and delayed the onset of diabetes [45]. OK-432 OK-432, a preparation of group A streptococcus pyrogens, has preventive effects on type 1 diabetes in NOD mice [46]. Two CU (clinical unit) of OK-432 were given intraperitoneally every week from 4 to 24 weeks of age. The administration of OK-432 suppressed the development of diabetes. Histological examination showed that in the OK-432-treated NOD mice, 98% of the islets were intact or mildly infiltrated with mononuclear cells. OK-432 has been reported to enhance interferon and IL-2 production and thus possibly normalizes lymphokine levels and suppressor activity in NOD mice.
s71 6 Makino.
Conclusion
S., Harada,
(1986) Absence
All these reports
strongly
nude mice with NOD
suggest that the dysfunc-
tion of IL-2 and its surface receptor tant role in the pathogenesis
though the precise mechanisms abnormality of the IL-2/IL-2R solved in type 1 diabetes,
Al-
responsible for the system remain un-
it is speculated
and
genetic
Y. and
overt
Hayashi
diabetes
background.
Y.
in athymic
Exp. Anim.
35.
495-498.
plays an impor-
of type 1 diabetes.
M.. Kishimoto.
of insulitis
that regu-
latory T cells demonstrating defective IL-2 production and H-IL-2R expression are capable of neither expanding clonally nor maturing functionally, allowing the generation of islet-specific autoreactive cells. Therefore, studies of the IL-2/IL-2R system, especially of the mechanism involved in the abnormal expression of IL-2R, have not only clarified the pathogenesis of type 1 diabetes, but may also have provided new reagents useful in the prevention and treatment of type 1 diabetes.
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