Disease relevance of RT1-Da

• Inbred diabetes-prone (DP) BioBreeding/Worcester (BB/Wor) (RT1u) rats develop spontaneous autoimmune diabetes, which, like human insulin-dependent diabetes mellitus, is mediated by autoreactive T lymphocytes [1].
• The body weights of the offspring segregated with the RT1 haplotype of the MHC, and the RT1l homozygotes were significantly smaller than their RT1l/u and RT1u/u littermates [2].
• We propose a disease model for the BB rat that requires 1) the RT1u MHC haplotype for disease susceptibility, 2) a new locus on chromosome 4 for disease initiation (as measured by insulitis), 3) a new locus on chromosome 13 for disease progression in response to environmental perturbation, and 4) lyp for spontaneous expression of disease [3].
• Adoptive transfer of T-cell clones expressing TCR Vbeta9 or Vbeta8.2, but not Vbeta4, to naive LEW animals elicited significant delayed-type hypersensitivity responses after challenge with the RT1.Dubeta20-44 peptide or allogeneic WF (RT1u) splenocytes [4].
• The data indicate that animals having pancreatic lymphocytic infiltration and insulinopenic overt diabetes mellitus had at least one RT1u haplotype [5].

High impact information on RT1-Da

• Concanavalin A-activated spleen cells from acutely diabetic DP rats adoptively transfer diabetes only to recipients that express at least one RT1u haplotype [1].
• Immune serum obtained from RT1u recipients that had rejected a RT1Aa disparate graft was able, when injected into cyclosporin-treated RT1u recipients, to restore their ability to reject a RT1Aa, but not a third-party RT1c, kidney [6].
• Injection of RT1u rats with MRC OX8 mAb was highly effective at selectively depleting CD8+ cells from graft recipients but had no effect in prolonging the survival of RT1Aa disparate grafts despite the complete absence of CD8+ cells from the graft infiltrate, which included numerous CD4+ T cells and macrophages [6].
• The testes of the RT1l animals showed an arrest of spermatogenesis at the early pachytene stage of the primary spermatocytes, and they were approximately 1/10 as heavy as the testes of the RT1l/u and RT1u/u animals [2].
• We used intra-RT1 recombinant rat strains with recombinations between the RT1a and RT1u haplotypes on the disease permissive LEW non-MHC genome [7].

Chemical compound and disease context of RT1-Da

• BACKGROUND AND OBJECTIVE: Comparative studies have shown that Wistar Ottawa Karlsburg W (RT1u) rats (WOKW) develop a nearly complete metabolic syndrome with obesity, moderate hypertension, dyslipidemia, hyperinsulinemia, and impaired glucose tolerance up to an age of 28 weeks [8].
• To evaluate the cellular origin of follicular dendritic cells (FDC) in lymphoid follicles (LFs), severe combined immunodeficient (SCID) mice (H-2d) were grafted with 5-bromo-2'-deoxyuridine (BrdU)-incorporated bone marrow cells from CB-17 mice (H-2d) and with non-BrdU-incorporated bone marrow cells from C3H mice (H-2k) and Wistar rats (RT1u) [9].

Biological context of RT1-Da

• We have found entire sequence identity between five different inbred rat strains of the RT1u haplotype, which differs from previously published, incomplete sequences [10].
• In a second experiment, rats from three strains that share the RT1u major histocompatibility complex haplotype of the BB/Wor and rats from three non-RT1u strains were lethally irradiated and reconstituted with DP BB/Wor bone marrow [11].
• Humoral responses to non-inherited maternal class I antigens (class I NIMAs) were assessed in 3 groups of inbred rats expressing the RT1u phenotype [12].
• In the fully major histocompatibility complex-disparate heart and skin transplantation models (LEW [RT1l]--> LEW.1W [RT1u]), a single dose of anti-RT7 mAb (10 mg/kg) was administered intravenously (day -1) [13].
• To evaluate whether in vivo immunogenicity of MHC peptides is relevant to tolerance induction and to examine the effect of peptide specificity, we compared the effects on graft survival of well-defined, strain-specific immunogenic WF MHC class I peptides (RT1.AU) with closely related but non-strain-specific class I peptides derived from WAG (RT1U) [14].

Anatomical context of RT1-Da

• Suppressor cells generated in cultures of WF (RT1u) with WRC stimulator cells potently suppressed a WF + WRCx test MLR, with less suppression when tested against either the WF + DAx or WF + BNx MLRs [15].
• Recipients that are RT1u at only the class I A or C locus, but not at the class II B/D loci, do not develop diabetes after T cell transfer [1].
• Genotypic mosaic rat livers were constructed by transplantation of carcinogen-altered F-344 (RT1Iv1) or WF (RT1u) donor liver cells into livers of WF X F-344 F1 host rats, whose liver cells bear alloantigens of both parental strains: WF and F-344, RT1u and RT1Iv1, respectively (J. M. Hunt et al., Cancer Res., 42: 227-236, 1982) [16].
• In immunohistochemistry using haplotype-specific antibodies, lymphocytes showed RT1u class I expression as in the normal WAG thymus [17].
• Streptozotocin-induced diabetic Lewis (RT1(1)) rats remained hyperglycemic (> 200 mg/dl) after intrahepatic preimmunization by injection of 200 low-temperature cultured (24 degrees C for 7 days) Wistar-Furth (WF, RT1u) rat islets into the portal vein with one injection (1 ml) of rat antilymphocyte serum intraperitoneally [18].

Associations of RT1-Da with chemical compounds

• Grafts (RT1u/l) of different cellular composition were intraportally transplanted in streptozocin-induced diabetic rats (RT1n/n) [19].
• Focusing on sex-difference in prolongation of allograft survival time, we have performed skin grafts between fully allogeneic rat strains, AO (RT1u) and DA (RT1a) with an immunosuppressant, cyclosporine [20].
• In addition, Wistar Furth (RT1u) rat recipients of Buffalo (RT1b) heart allografts were treated with FTY720 alone or in combination with other agents [21].
• Both AO (RT1u) and DZB (RT1u) rats were found to develop a membranous autoimmune glomerulopathy upon exposure to HgCl2 [22].
• Fetal ventral mesencephalic tissue containing DA neuroblasts from Wistar-Furth (WF, RT1u) rat donors (9-12 mm CRL) were later implanted in striatum on the lesioned side [23].

Other interactions of RT1-Da

• Here we describe the complementary DNA (cDNA) sequence encoding the alpha and beta chains of both the RT1-B and RT1-D locus genes of the rat RT1u haplotype [10].
• Serological characterization of rat class II (RT1.B) alloantigens. Analysis of the RT1l, RT1u, and RT1n haplotypes [24].

Analytical, diagnostic and therapeutic context of RT1-Da

• We utilized neonatal tolerance induction to prevent rejection of Wistar-Furth (WF) (RT1u) islet allografts by spontaneously diabetic BB recipients [25].
• Purified islets from neonatal F-344 (RT1Lv1) rats were transplanted bilaterally under the kidney capsule of Wistar-Furth (W/F, RT1u) rats without immunosuppression [26].
• Primary anti-MHC class I alloantibody responses, detected by indirect hemagglutination and complement-dependent cytotoxicity assays, were abrogated in high-responder WAG (RT1u) recipients of DA (RT1a) blood transfusions, given on days 0 and 7 of a 14-day course of rapamycin (3 mg/kg/day) [27].
• Brown Norway (RT1n) to Lewis (RT1(1)) combination was used in the heart and pancreas transplantation models, whereas Buffalo (RT1b) to Wistar Furth (RT1u) was used in the kidney transplantation model [28].
• Isografts of 1500 freshly isolated (n = 8) or 2500 frozen-thawed (n = 6) Wistar-Furth (RT1u/u) islets induced long-term normoglycemia after intrathymic transplantation (median survival time [MST] > 100 days in both groups), whereas isografts of 1500 frozen-thawed islets (n = 5) were inconsistent in restoring long-term normoglycemia [29].

References