Multiple injections of subdiabetogenic doses of streptozotodn (SZ) to CD-I male mice produce a diabetic syndrome that includes a cell-mediated immune reaction against the pancreatic islet. The importance of the host genetic background in the pathogenesis of this model of diabetes was studied by comparing various inbred strains of mice. Of eight strains of mice studied, only C57BL/KsJ developed insulitis and hyperglycemie comparable to that observed in CD-I mice. In two mouse strains (DBA/2J and BALB/cJ) having an haplotype similar to the C57BL/KsJ, only mild insulitis and glucose intolerance were observed. These data suggest that major histocompatibility complex genes, as presently defined, cannot be the only determinant of the severity of hyperglycemia and insulitis in this model.
To determine the influence of infectious agents on the initiation of diabetes in the spontaneously diabetic Bio-Breeding/Worcester (BB/W) rat, susceptible rats were raised in a germ-free environment. Between 2 and 3 mo of age, 3 of 12 pups became diabetic. Histologic examination of the pancreas revealed insulitis or end-stage islets. Culture and smears from various tissues were negative for bacteria or parasites. Serum vital antibody titers for all known rat viruses were undetectable. These data suggest that the diabetic syndrome of the BB/W rat is not dependent on recognized infectious agents.
The BioBreeding Rat is a recently discovered model of spontaneous diabetes mellitus. Studies to date have revealed the following characteristics of the syndrome: genetic predisposition, equal frequency and severity among males and females, absence of obesity, life sustaining requirement for insulin therapy, lymphocytic insulitis with destruction of pancreatic beta-cells, lymphocytic thyroiditis and the presence of autoantibodies to smooth muscle, thyroid colloid and other cellular antigens. Animals raised in a germ-free environment evidence diabetes with equal frequency and severity. Support for a cell-mediated autoimmune pathogenesis of the diabetic syndrome is derived from the following experiments: administration of antiserum to rat lymphocytes prevents diabetes in susceptible animals and normaliies plasma glucose levels in 36% of diabetic rats; neonatal thymectomy almost completely prevents the occurrence of diabetes. Although the BB rat may not be an appropriate model for studying the vascular complications of diabetes, peripheral nerve functional and ultrastructural defects have been reported and renal glomerular immuneglobulin deposits have been observed in long-term diabetic animals.
Abstract Antigen altered idiotype regulates specific immune responses. Mendelian segregation of a given +/- phenotype defines an immune response gene (IR-X) . Autoimmunity producing anti-self clones must be eliminated or specifically suppressed, so a large portion of the antigenic repertoire resembles allogeneic MHC molecules. Singer and Williams (Cell Immunol.1978: 4:1) proposed that exposure to many allogeneic HLA molecules could eventually overlap with important responses to pathogens, causing serious holes in the repertoire, some large enough to produce an acquired immunodeficiency syndrome (AIDS). The changes resulting from exposure to multiple incompatible allogeneic MHC molecules could also produce the opposite effect, an increase in a desirable immune response, or the allogeneic effect . IR-genes for histocompatible tumor resistance localized to the mouse MHC (Cancer Res. 1975;35:1586) The patient with HIV and AML, who was rendered free of both by transplantation of the right allogeneic stem cells (Blood,2010,Dec 8) supports our case. We propose that HIV is a unique and potent inducer of altered idiotype immune suppression. Explanation of the mechanism for synthetic antigens by Benacerraf (Nobel, 1980) and for viruses by Zinkernagel and Doherty (Nobel, 1986) followed from the idiotype network concept of Jerne (Nobel, 1984). Our attempt to relate these observations to the MHC and genetically controlled immune responses led us to the altered idiotype hypothesis.
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