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Diabetes 53:3115-3119, 2004
© 2004 by the American Diabetes Association, Inc.

Absence of Lymph Nodes in NOD Mice Treated With Lymphotoxin-ß Receptor Immunoglobulin Protects From Diabetes

Matteo G. Levisetti1,2, Anish Suri2, Katherine Frederick2, and Emil R. Unanue2

1 Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri


   ABSTRACT
TOP
 ABSTRACT
RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pregnant nonobese diabetic (NOD) mice were treated with lymphotoxin-ß receptor immunoglobulin fusion protein (LTßR-Ig) or control human immunoglobulin on days embryonic day 11 (E11) and E14, and offspring were followed for the development of anti–ß-cell antibodies, islet pathology, and hyperglycemia. The development of anti–ß-cell surface antibodies was abrogated in treated mice compared with controls. Autopsy examination of the mice at 30 weeks of age revealed normal development of secondary lymphoid structures in the control animals; however, mice treated with LTßR-Ig had no axillary, inguinal, popliteal, or peripancreatic lymph nodes. Histological examination of the pancreata of the control mice revealed a severe and destructive mononuclear cellular infiltrate in the islets, whereas the islets of the LTßR-Ig–treated mice were devoid of any insulitis. None of the LTßR-Ig–treated mice (n = 22) developed diabetes; in contrast, 80% of the control mice (n = 46) developed diabetes at 1 year of age. The LTßR-Ig–treated mice did not contain diabetogenic T-cells. However, the treated mice developed diabetes upon inoculation with diabetogenic T-cells. In this model of spontaneous autoimmune diabetes, secondary lymphoid structures, most likely the peripancreatic lymph nodes, were essential for the development of pathologic anti–ß-cell autoimmunity.

Recent studies have demonstrated an important role for local lymph nodes in the pathogenesis of tissue-specific autoimmune disease. For example, in a mouse model of autoimmune arthritis, the inhibition of lymph node development by in utero administration of lymphotoxin-ß receptor-immunoglobulin fusion protein (LTßR-Ig) delayed and attenuated the course of disease (1). We chose to investigate the role of peripheral lymph nodes in the pathogenesis of autoimmune diabetes in the nonobese diabetic (NOD) mouse model of the disease using a similar approach. The peripancreatic lymph nodes accumulate diabetogenic T-cells and may be their major site of priming and activation (2–5). Moreover, surgical excision of the peripancreatic lymph nodes delayed and decreased the incidence of diabetes in NOD mice (6). The present study administering LTßR-Ig to pregnant NOD mice was initiated just at the time of the report on surgical excision of peripancreatic lymph nodes. Our studies in "nodeless" mice induced by LTßR-Ig confirm and extend these results.

The essential role of the lymphotoxin (LT)ß signaling pathway in lymphoid organogenesis was revealed by the analysis of mutant mice in which LTß signaling did not take place: LTßR (LTß receptor)-deficient, LT{alpha}-deficient, and LTß-deficient mice failed to develop lymph nodes (7–11). Moreover, the LTß system also plays a crucial role in the establishment and maintenance of the organized lymphoid structures that are present in tissue-specific autoimmune disease. The therapeutic effects of LTßR-Ig have been studied in rodent models of arthritis, experimental autoimmune encephalomyelitis, colitis, uveitis, and autoimmune diabetes (12–16). In a report from Bluestone and Fu’s (16) laboratories, administration of the LTßR-Ig inhibited the development of diabetes and actually reversed active inflammation. Diabetogenic T-cells transferred into nondiabetic mice together with the fusion protein failed to induce diabetes. In entirety, their results indicated that the development of the lymphocytic lesion that develops in the NOD mouse required LTß signaling. Results similar to these were obtained from McDevitt’s group (17) but using transgenic mice that expressed the LTß fusion protein. Our studies differ from these two in that the mice were exposed to the soluble decoy receptors during gestation, disrupting lymph node development but leaving LTß signaling intact in the adult mice (18).


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
NOD mice were originally obtained from The Taconic Laboratory and NOD.scid mice from The Jackson Laboratory (Bar Harbor, ME). Mice were followed for the development of diabetes by bimonthly blood glucose measurement, and diabetes was defined by values >250 mg/dl on two separate occasions. All mice were housed and cared for in accordance with the guidelines of the Washington University Committee for the Humane Care of Laboratory Animals and with the National Institutes of Health guidelines on laboratory animal welfare.

LTßR-Ig treatment.
Timed pregnant NOD females were injected with 100 µg i.v. LTßR-Ig (gift of J. Browning, Biogen, by way of Drs. Laura Mandik-Nayak and Paul Allen) or control human immunoglobulin (Jackson Immuno-Research) on embryonic day 11 (E11) and E14 as described (18).

Cell lines and antibodies.
The NIT-1 cell line (19) was a gift from Dr. E.H. Leiter (The Jackson Laboratory). The monoclonal antibody SF1.1.1 was used to stain H-2Kd (Pharmingen, San Diego, CA).

Fluorescence-activated cell sorter analysis of serum antibodies.
NIT-1 cells were incubated first with mouse sera and then with a goat anti-mouse IgG-PE (Caltag, Burlingame, CA). Fluorescence-activated cell sorter (FACS) analysis was performed on a FACScan flow cytometer, and data analysis was performed with CellQuest software (Becton Dickinson, Mountain View, CA).

Histology and immunohistochemistry.
Mice were killed by cervical dislocation, and pancreata were fixed in 10% formalin and then stained with hematoxylin and eosin. The spleens of control and nodeless animals were frozen and then stained with anti–CD3-FITC (fluorescein isothiocyanate) and anti–CD19-PE (Pharmingen).

Transfer into NOD.scid recipients.
Splenocytes (2 x 107) from control and nodeless mice were transferred into NOD.scid recipients by intravenous tail vein injection. The mice were followed by blood glucose determination every 1–2 weeks.

Transfer of splenocytes into control and nodeless mice.
Nodeless mice and 8-week-old NOD male mice were irradiated with 600 R and then received 3 x 107 splenocytes from diabetic NOD donors by intravenous tail injection.


   RESULTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
LTßR-Ig–treated mice fail to develop lymph nodes.
Mice from control immunoglobulin and LTßR-Ig–treated mothers were examined for the presence of lymph nodes. As previously reported, LTßR-Ig–treated mice were born without axillary, inguinal, and popliteal lymph nodes (18) and also lacked peripancreatic lymph nodes. The absence of peripancreatic lymph nodes was confirmed by en block resection and careful histological analysis of tissue containing the duodenum and head of the pancreas, including the superior mesenteric vessels. The spleens from the two groups of animals had normal cellularity and architecture (Figs. 1A and B). Specifically, there was no significant difference in the total number of cells or in the number of T-cells, B-cells, dendritic cells, and macrophages between the two groups of animals. The gross architecture of the spleens was preserved as demonstrated by normal appearing T- and B-cell zones.



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  		FIG. 1. LTßR-Ig–treated animals had normal splenic cellularity and architecture. The cellularity of the spleens from control immunoglobulin and LTßR-Ig mice were not different from one another (A). There was no statistically significant difference in the total number of cells or in the numbers of T-cells, B-cells, dendritic cells, and macrophages. The architecture of the spleens appeared normal in the nodeless mice. The white pulp contained a normal appearing periarteriolar lymphoid sheath (anti–CD3-FITC ([fluorescein isothiocyanate]: green) surrounded by normal appearing B-cells (anti–CD-19-PE: red) (B).

 
LTßR-Ig treatment prevents diabetes.
The offspring of LTßR-Ig–treated mice were followed for the development of hyperglycemia by weekly blood glucose measurement. Control mice developed diabetes with kinetics and a cumulative incidence equivalent to that found in our NOD mouse colony, with an incidence of 80% (36 of 46) at 1 year of age (Fig. 2). In contrast, none of the mice (0 of 22) of LTßR-Ig–treated mothers developed diabetes at 1 year. The pancreata of mice from both control and LTßR-Ig mice were examined histologically for the presence of inflammation and ß-cell death. The control mice all developed a destructive inflammatory infiltrate, with marked loss of ß-cell mass; in contrast, the islets from the LTßR-Ig–treated mice were devoid of infiltrate (Fig. 3). A weak peri-insulitis was found in the pancreas of some of the nodeless mice after 40 weeks of age; however, ß-cell mass was preserved in these animals.



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  		FIG. 2. Treatment with LTßR-Ig prevented diabetes. The cumulative incidence of diabetes in controls ({blacktriangleup}, n = 46) and LTßR-Ig–treated animals ({blacksquare}, n = 22) is presented above. At 1 year of age the incidence in control animals, males and females combined, was 80%, while none of the nodeless animals developed disease.

 


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  		FIG. 3. Nodeless mice failed to develop insulitis. The islets of control mice developed a severe inflammatory infiltrate and marked loss of ß-cell mass. The islets in the nodeless NOD mice were free of infiltrate, and ß-cell mass was preserved. The histology shown above was taken from female animals at 30 weeks of age.

 
The development of anti–ß-cell surface autoantibodies is attenuated by LTßR-Ig treatment.
The NOD mouse spontaneously develops antibodies that bind to ß-cell surface antigens between 4 and 8 weeks of age (20). To determine the role of lymph nodes in this process, control and experimental animals were examined for the presence of anti–ß-cell autoantibodies at various time points. Serum antibody titers were assessed by flow cytometric analysis of NIT-1 cells stained with mouse serum and expressed as mean fluorescence intensity. At the time points examined (6, 10, and 30 weeks of age), the development of anti–ß-cell antibodies was reduced by approximately half in the LTßR-Ig–treated group when compared with control animals (P < 0.05, Table 1). Of note, LTßR-Ig–treated mice did develop low titers of ß-cell autoantibodies, as demonstrated by positive staining when compared with nonautoimmune strains of mice, such as B10.BR mice.


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  		TABLE 1 Attenuation of anti–ß-cell antibodies in LTßR-Ig–treated mice

 
LTßR-Ig–treated mice do not harbor diabetogenic T-cells.
To determine whether protected mice contained T-cells capable of inducing diabetes, splenocytes from LTßR-Ig–treated mice were transferred into NOD.scid recipients. Splenocytes from LTßR-Ig–treated mice failed to transfer diabetes into NOD.scid recipients compared with controls. Splenocytes from diabetic control mice induced diabetes in all (13 of 13) recipients by 8 weeks posttransfer; however, splenocytes from nodeless mice induced diabetes in only 1 of 13 recipients at 25 weeks posttransfer (Fig. 4A). These results taken together indicate that the presence of secondary lymphoid organs plays a key role in the expansion and/or maintenance of a diabetogenic T-cell repertoire. However, the defect in T-cell development is not global, as demonstrated in experiments where NOD and nodeless mice were immunized with the protein antigen hen-egg white lysozyme intraperitoneally and the spleen T-cells were then tested for proliferation. Cells from both control and LTßR-Ig–treated mice proliferated to hen-egg white lysozyme, indicating that T-cells could respond in an antigen-specific manner to systemic immunization. Moreover, these findings are consistent with previously published data in similar model systems (13,14,21).



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  		FIG. 4. The diabetogenic potential of splenocytes from nodeless mice was reduced. All NOD.scid recipients of splenocytes (2 x 107) from control immunoglobulin mice (13 of 13) developed diabetes by 8 weeks posttransfer. Only one (1 of 13) of the NOD.scid recipients of splenocytes (2 x 107) from nodeless NOD mice developed diabetes at 25 weeks posttransfer (A). Nodeless NOD mice were susceptible to the adoptive transfer of diabetes. The transfer of diabetic splenocytes (2 x 107) into irradiated control and nodeless NOD mice induced diabetes with similar kinetics and cumulative incidence (B).

 
However, the ability of splenocytes from diabetic NOD mice to induce diabetes upon transfer into nodeless NOD mice was no different from controls (Fig. 4B). By 8 weeks posttransfer, 60% (3 of 5) had developed disease in the two groups, indicating that the peripancreatic lymph nodes are dispensable for the adoptive transfer of diabetes induced by primed T-cells.


   DISCUSSION
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study, in conjunction with others (3,6,22), reveals the critical importance of secondary lymphoid structures, most likely the peripancreatic lymph nodes, in the pathogenesis of autoimmune diabetes in the NOD mouse. Mice without lymph nodes were completely protected from the development of diabetes and had reduced anti–ß-cell autoantibodies and reduced numbers of pathogenic T-cells.

The complete protection from disease enjoyed by the nodeless mice is very likely the result of the interruption or prevention of a critical step in the disease process, namely the priming and expansion of ß-cell–specific pathogenic T-cells, an event that requires the local concentration of diabetogenic antigens in the milieu of a lymph node. The failure of splenocytes from nodeless animals to transfer disease (1 of 13 at 25 weeks posttransfer) supports the conclusion that ß-cell–reactive T-cells were not primed in the nodeless animals or that T-cells existed at a low frequency incapable of inducing disease when transferred into NOD.scid mice.

In contrast to the surgical removal of the peripancreatic lymph nodes at 3 weeks of age, which reduced the incidence of diabetes to ~20% at 30 weeks of age, (6) LTßR-Ig treatment provided complete protection from diabetes for over 1 year. It is possible that the critical priming event, presumably the encounter of ß-cell–specific T-cells with antigen-presenting cells bearing relevant ß-cell antigens, may occur before 21 days of age in a subset of animals. Interestingly, the nodeless mice produced anti–ß-cell antibodies, although at half the titers compared with controls, while the mice treated with splenectomy had greatly reduced titers of anti-insulin antibodies. Taken together, these results clearly reveal the important role played by both the spleen and the peripancreatic lymph nodes in the production of a vigorous anti–ß-cell humoral response.

Finally, as in the study of Gagnerault et al. (6), diabetes developed after the transfer of T-cells into the nodeless mice. This is an indication that the recognition by T-cells of diabetogenic antigens can take place in at least two sites, the local draining lymph node or the pancreas—the former is the favorable site for priming, the latter for the recruitment and development of already-activated T-cells. The peripancreatic node contains diabetogenic T-cells and is indispensable for T-cell induction, as the Gagnerault study and ours indicate (although the mice in our study have a complete absence of lymph nodes). In contrast, the islets can be infiltrated by diabetogenic T-cells independent of lymph nodes, indicating that primed T-cells do not require an intermediate migration through local nodes. The important question of whether the diabetogenic T-cell recognizes the antigen-presenting cells around the islets or within them needs to be determined.

Although the molecular identity of ß-cell antigens relevant to disease pathogenesis have yet to be fully elucidated, this study, in addition to others, identifies the local lymph nodes as the critical site of T-cell priming. This knowledge of the anatomy of the disease process will hopefully facilitate the identification of disease relevant autoantigens.


   ACKNOWLEDGMENTS
 
M.G.L. was supported by a grant from the Howard Hughes Medical Institute to Washington University.

The authors thank Dr. Jeffrey L. Browning for the LTßR-Ig and Gina Filley for technical assistance.


   FOOTNOTES
 
LTßR-Ig, lymphotoxin-ß receptor immunoglobulin fusion protein.

Address correspondencereprint requests to Emil R. Unanue, MD, Campus Box 8118, 660 S. Euclid Av., St. Louis, MO 63110. E-mail: unanue{at}pathology.wustl.edu

Received for publication March 29, 2004 and accepted in revised form September 1, 2004


   REFERENCES
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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