Influence of islet and bone marrow transplantation on the diabetes and immunodeficiency of BB rats

doi:10.1016/S0026-0495(83)80013-4

Metabolism

Volume 32, Issue 7, Supplement 1, July 1983, Pages 62-68

https://doi.org/10.1016/S0026-0495(83)80013-4 Get rights and content

The results of islet transplantation in spontaneous autoimmune diabetes of BB rate were studied to determine whether this disease process might damage the transplanted islet tissue. Since BB rats are not genetically uniform, syngenetic grafts could not be used; therefore, allograft rejection was provented by rendering BB rats immunologically tolerant of WF transplantation antigens by neonatal inoculation with bone marrow cells. Despite the resultant tolerant stato, which permitted successful engraftment of WF skin allografts, the transplanted islets amellorated the spontaneous diabetes of BB rats only briafly before they were destroyed by immune insulitis. BB rats from the diabetic stock were found to suffer from abnormalities in T lymphocytes and their subsets as well as defective immune response patterns. When analyzed with monoclonal antibodies specific for rat lymphocyte markers, BB rats of the diabetic stock were found to be lymphocytopenic. There was a reduction in heiper T cells and a more severe deficit in the suppressor/cytotoxia subset. BB rats that were inoculated neonatally with bone marrow from normal donors were found to have a strikingly reduced incidence of diabetes. Moreover, the T cell functional, numerical, and microenvironmental defects that were present in noninoculated BB rats were restored in marrow-inoculated BB rats, findings possibly related to the decreased incidence of diabetes.

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Preclinical experiments
2004, Best Practice and Research: Clinical Haematology
The clinical use of autologous stem cell transplants for the treatment of refractory severe autoimmune diseases was preceded by convincing proof of its underlying principle in animal models. The various categories of experimental autoimmune disease in laboratory rodents are briefly described here, and the rationale that was used in the selection of suitable experimental autoimmune diseases for translational research is explained. The two models that provided the bulk of the data needed for designing the initial clinical treatment protocols were adjuvant arthritis (AA) and experimental allergic encephalomyelitis (EAE), which were both induced in Buffalo rats. In this strain, AA is manifested as a chronic, progressive, systemic polyarthritis and EAE as a chronic, remitting/relapsing form of encephalomyelitis resembling multiple sclerosis. Both diseases can be cured with autologous stem cell transplantation provided that adequate conditioning is given and that the disease has not yet progressed to the stage of ‘scarring’. It is basically the inflammatary stages that respond well to this therapy. The success of treatment depends on how completely the autoantigen-specific activated T-lymphocytes and memory cells are eradicated. Because of a lack of information on the nature of the autoantigens involved in human disease and on the size of those cell populations in the animal models as well as in humans, this aspect of translation is difficult. The experiments have, however, provided important guidelines. High-dose conditioning regimens yield better results than low-dose conditioning, certain conditioning agents perform better than others, and care should be taken not to reintroduce too many T-cells with the autologous graft. The clinical results obtained so far indicate a high predictive power of these two animal models, which are therefore recommended strongly for additional preclinical studies.
Direct and indirect pathways of immunity to pancreatic islet transplants
1998, Transplantation Reviews
New opportunities for the treatment of severe autoimmune diseases: Bone marrow transplantation
1998, Clinical Immunology and Immunopathology
Insulin dependent diabetes mellitus, an autoimmune disorder?
1989, Clinical Immunology and Immunopathology
During the last 25 years the concept of a chronic autoimmune process leading to the development of insulin dependent diabetes (IDD) has emerged. The presence of two animal models for IDD, the BB rat and the NOD mouse, has improved our ability to understand the process leading to β cell destruction. The hallmark of an autoimmune disease is the characteristic pathologic lesion of mononuclear infitration of the pancreatic islets. Further histologic studies of the diabetic pancreas have identified the type of cells infiltrating the islets and led to the concept of pancreatic β cells capable of presenting antigen. The initial description of linkage disequilibrium of HLA DR3 and DR4 alleles with IDD has now progressed to the molecular level with the identification of residue 57 of the HLA DQ β chain as crucial to the genetic predisposition to IDD. Autoantibodies to cytoplasmic antigens (ICA), surface antigens, or a membrane protein of 64 kDa identified by immunoprecipitation, autoantibodies to secreted products such as insulin and proinsulin, and autoantibodies that are cytotoxic to cultured β cells are islet specific autoantibodies that have been described. Some are probably only markers of immunologic activity; others might participate in the destruction itself. The use of ICA as a screening tool has been successful in identifying individuals prior to the onset of IDD. Widespread cellular immunological defects have been identified both in animal models and in man. In the BB rat, a seeming paradox of severe immunodeficiency occurs in an animal with autoaggressive destruction of β cells. More subtle defects in immuno-regulation have been described in the NOD mouse and in human IDD. The response of IDD in both animal models and in man to immunomodulation and to immunosuppression offers further evidence of an immunologically mediated disease. However, some therapies in the animal models, not typically considered immunologic, such as protein restriction and insulin therapy, have prevented IDD. The possibility of intervening prior to the onset of clinical disease at the level either of the initial process of recognition of the pancreatic β cell as a target organ or of the effector mechanism is approaching a reality in human IDD.
Immunological aspects of diabetes mellitus: Prospects for pharmacological modification
1989, Pharmacology and Therapeutics
It is now well known that insulin-dependent diabetes is a chronic progressive autoimmune disease. The prolonged prediabetic phase of progressive β-cell dysfunction is associated with immunological abnormalities. A prediabetic period is suggested by the appearance of islet cell antibodies, anti-insulin antibodies, and anti-insulin receptor antibodies. The existence of activated T lymphocytes and abnormal T cell subsets are also other markers. There is still no concensus about the use of the immunosuppression superimposed upon conventional insulin therapy in early diagnosed IDDM and the follow-up of the relatives of IDDM patients who share the genetic predisposition and serological markers for the risk of future onset of IDDM. Treatment in the prodromal period cannot be justified because a link between the disease and early markers such as ICA has not been established with certainty (Diabetes Research Program NIH, 1983). Many immunopharmacological manipulations were reported to be effective in animal models. However, most of them are not readily applied to human subjects. Morever, IDDM patients are now believed to be heterogeneous, with a complex genetic background. HLA-DR, and more recently DQ, are closely related to the genetic predisposition to IDDM but those genes are not themselves diabetogenic. The contribution of autoimmunity does not appear to be uniform, and in some cases, the contribution of virus is considered more important. There is a lack of a marker for the future onset of IDDM. ICA and ICSA were found after mumps infection, but the existence of those autoantibodies and even the co-existence of HLA-DR3 do not always indicate the future trend to insulin dependency. More precise markers will be disclosed through the biochemical analysis of the target antigens on pancreatic β-cell for islet antibodies and effector T cells. Much safer and more effective immunopharmacological treatment will be developed through animal experimentation using rat and mouse models. The recent development and interest in this field will further facilitate the attainment of the goal or the complete prevention of IDDM.
Autoimmune Endocrine Disease
1985, Vitamins and Hormones
This chapter discusses autoimmune endocrine disease. Many different definitions of autoimmune disease exist. From a pathophysiological point of view, autoimmune disease represents altered physiology as a direct result of antibodies or lymphocytes reacting with self antigens. From an immunological point of view, autoimmune disease should be transferable with antibodies or lymphocytes, and the disease process should be reenacted in normal transplanted tissue without evidence of tissue rejection. From a clinical point of view, autoimmune disease should be preventable or curable with immunotherapy. As the study of endocrine autoimmunity as well as other autoimmune diseases has progressed, many common themes link these various illnesses. There are three major pathogenic mechanisms in autoimmune endocrine disease. The most common cause of disease is the destruction of a specific gland or cell type (type I diabetes mellitus, thyroiditis, idiopathic primary adrenal insufficiency, idiopathic hypoparathyroidism, primary gonadal insufficiency, and hypophysitis). The next most common cause of autoimmune endocrine disease results from antibody interactions with cell-surface receptors either mimicking hormone action (Graves' disease, hypoglycemia with anti-insulin receptor antibodies) or blocking receptor function (atrophic hypothyroidism and insulin resistance secondary to anti-insulin receptor antibodies).

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^*: Supported in part by grants USPHS AM26007 and CA18640 and by the Reynolds Foundation and the McCabe Fund.

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Influence of islet and bone marrow transplantation on the diabetes and immunodeficiency of BB rats*

Pancrease and islet transplantation. II. Clinical trials

Diabetologia

Spontaneous diabetes in rats: Destruction of islets is prevented by immunological tolerance

Science

Successful islet transplantation in spontaneous diabetes

Surgery

Monoclonal antibodies that define T-lymphocyte subsets in the rat

Spontaneous diabetes in BB rats: Evidence for a T cell dependent immune response defect

Diabetologia

Prevention of diabetes in rats by bone marrow transplantation

Ann Surg