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D L Faustman

Publications and source records attributed to D L Faustman.

At least 19 recordsLinked to original sources
PubMed2005

The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis.

Excess levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with certain autoimmune diseases. Under the rationale that elevated TNF-alpha levels are deleterious, several anti-TNF-alpha therapies are now available to block the action of TNF-alpha in patients with autoimmune diseases with a chronic inflammatory component to the destructive process. TNF-alpha antagonists have provided clinical benefit to many patients, but their use also is accompanied by new or aggravated forms of autoimmunity. Here we propose a mechanistically based hypothesis for the adverse events observed with TNF-alpha antagonists, and argue for the opposite therapeutic strategy: to boost or restore TNF-alpha activity as a treatment for some forms of autoimmunity. Activation defects in the transcription factor nuclear factor kappaB leave autoreactive T cells sensitive to TNF-alpha-induced apoptosis. Treatment with TNF-alpha, by destroying autoreactive T cells, appears to be a highly targeted strategy to interrupt the pathogenesis of type 1 diabetes, lupus and certain forms of autoimmunity.

Animals↗
PubMed2003

Central role of defective apoptosis in autoimmunity.

Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development likely induces cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accelerated apoptosis, are now demonstrated as central defects in diverse murine autoimmune disease. In murine models of autoimmune lupus, mutations in cell death receptor Fas (CD95) and its ligand, FasL (CD95 L), have been identified. These errors create a lymphoid system resistant to apoptosis. In contrast, select lymphoid subpopulations of maturing autoimmune prone non-obese diabetic mice have identifiable and pathogenic T cells with both in vivo and in vitro heightened apoptosis after drug interventions. In part, these defects are due to faulty activation of transcription factors such as nuclear factor-kappaB (NF-kappaB) that normally protect against apoptotic death. The genetic basis of interrupted NF-kappaB in pathogenic memory T cells in diabetes is attributable to a developmentally controlled gene defect in an essential subunit of the proteasome. No specific gene in most common forms of human autoimmune disease has yet been identified. Functional assays from diverse laboratories repeatedly demonstrate heightened apoptosis in multiple cellular signaling pathways for cell death, suggesting a common theme in disease causality.

Animals↗
PubMed2001

Selected contribution: Association of gender-related LMP2 inactivation with autoimmune pathogenesis.

Recent results in an animal model of autoimmune diabetes, the nonobese diabetic (NOD) mouse, suggest a hypothesis to explain the role of major histocompatibility complex (MHC) in autoimmunity. The genome MHC region contains immune response genes that are important for T cell education and antigen presentation by MHC molecules. Two such genes encoding the LMP2 and LMP7 proteasome subunits are located in this high-risk MHC genomic region. Proteasome containing the LMP2 subunit is essential for T cell education and proteolytically activates transcription factor nuclear factor-kappaB. Splenocytes of NOD mouse with marked female specificity for disease expression are defective in LMP2 expression. The spontaneous defective LMP2 expression in NOD mice, which is gender biased toward female cohorts, is restricted to select lymphoid and myeloid cells and is developmentally controlled with lowered LMP2 protein and heightened tumor necrosis factor-alpha-induced apoptosis. These defects are apparent only after approximately 7 wk of age. These data suggest a proteasome role in autoimmune progression, and a gender developmental and lineage restriction of LMP2 expression may contribute to the diverse autoimmune characteristics preferentially observed in female NOD mice.

Animals↗
PubMed2001

Reversal of established autoimmune diabetes by restoration of endogenous beta cell function.

In NOD (nonobese diabetic) mice, a model of autoimmune diabetes, various immunomodulatory interventions prevent progression to diabetes. However, after hyperglycemia is established, such interventions rarely alter the course of disease or allow sustained engraftment of islet transplants. A proteasome defect in lymphoid cells of NOD mice impairs the presentation of self antigens and increases the susceptibility of these cells to TNF-alpha-induced apoptosis. Here, we examine the hypothesis that induction of TNF-alpha expression combined with reeducation of newly emerging T cells with self antigens can interrupt autoimmunity. Hyperglycemic NOD mice were treated with CFA to induce TNF-alpha expression and were exposed to functional complexes of MHC class I molecules and antigenic peptides either by repeated injection of MHC class I matched splenocytes or by transplantation of islets from nonautoimmune donors. Hyperglycemia was controlled in animals injected with splenocytes by administration of insulin or, more effectively, by implantation of encapsulated islets. These interventions reversed the established beta cell-directed autoimmunity and restored endogenous pancreatic islet function to such an extent that normoglycemia was maintained in up to 75% of animals after discontinuation of treatment and removal of islet transplants. A therapy aimed at the selective elimination of autoreactive cells and the reeducation of T cells, when combined with control of glycemia, is thus able to effect an apparent cure of established type 1 diabetes in the NOD mouse.

Adoptive Transfer↗
PubMed1997

Reduced expression of Tap1 and Lmp2 antigen-processing genes in the nonobese diabetic (NOD) mouse due to a mutation in their shared bidirectional promoter.

The MHC is an essential contributor to autoimmunity. Lmp2 and Tap1 are genes located in the MHC class II region, and they encode proteins participating in the generation and transport of endogenous peptides for T cell education. A mutation (T-->A) has now been detected in the shared bidirectional promoter of the Lmp2 and Tap1 genes in the nonobese diabetic (NOD) mouse. The nucleotide substitution (TCATTC-->TCAATC) in NOD mice eliminates an initiator (Inr) element (TCATTC) thought to be important for RNA polymerase II positioning in the Lmp2 orientation. It also created a CAAT-like box and an inverted CAAT-like box in the Lmp2 and Tap1 orientations, respectively. Northern blot revealed reduced amounts of Tap1 and Lmp2 mRNA in NOD mice, and 5'-rapid amplification of cDNA ends revealed the loss of a transcription start site of Lmp2 in these animals. The Tap1-Lmp2 promoter from NOD mice showed reduced transcriptional activity in transient transfection assays with luciferase reporter constructs for both Tap1 and Lmp2 genes. Observed altered substrate specificity of Lmp2 containing proteasomes isolated from NOD mice was consistent with reduced Lmp2 activity. The beneficial influence of non-MHC genes (NOR mice) and gender factors (male NOD mice) influencing the penetrance of the promoter polymorphism further confirmed the essential gender and hormonal context of the mutation. This study identifies the first specific mutation in the MHC of the NOD mouse that specifically impacts the activity of genes involved in peptide presentation, a process essential for T cell education.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Screening of the TAP1 gene by denaturing gradient gel electrophoresis in insulin-dependent diabetes mellitus: detection and comparison of new polymorphisms between patients and controls.

New protective or disease-associated polymorphisms in the TAP1 gene were sought in insulin-dependent diabetes mellitus (IDDM) patients with the use of denaturing gradient gel electrophoresis (DGGE) screening of genomic DNA. The TAP1 gene is located in the human leukocyte antigen (HLA) class II region of the genome and encodes components of a peptide transporter essential for antigen presentation by HLA class I molecules. Fragments of TAP1 corresponding to the 5' promoter, each of the 11 exons (with portions of adjacent intronic regions) and the 3' flanking region were amplified by the polymerase chain reaction and then subjected to DGGE. DNA fragments of TAP1 yielded DGGE bands with patterns whose frequencies differed between IDDM patients and controls. Specific DGGE band patterns with fragments corresponding to the promoter, exons or introns 3, 6, 7, 8, 9 or 10 of TAP1 were detected exclusively in either patients or controls. Sequencing of TAP1 fragments encompassing exon 7 gave rise to a DGGE band pattern exclusively observed in an IDDM patient and sequencing revealed a previously unidentified polymorphisms at codon 518 (GTC-->ATC, Val-->Ile). Another unique polymorphism uncovered by DGGE revealed by sequencing a polymorphism in intron 2 in a diabetic patient. The genotypes of additional HLA class II matched patients and controls were determined with regard to five exonic and one intronic TAP1 polymorphism. A 10 base pair intronic insertion in intron 9 was exclusively identified in controls and missing from patients (P = 0.017). Further large population-based studies may reveal whether these newly identified at risk or protective TAP1 variants confer markers of statistical risk in diverse population groups.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Reduced expression of peptide-loaded HLA class I molecules on multiple sclerosis lymphocytes.

Lymphocytes from patients with HLA class II-linked autoimmune diseases such as type I diabetes, systemic lupus erythematosus, rheumatoid arthritis, and Graves' have recently been shown to have a decrease in the expression of self-peptide-filled HLA class I antigens on the surface of peripheral lymphocytes. The human demyelinating diseases of multiple sclerosis in some cases are also associated with the presence of certain HLA class II genes, which may in turn be linked to genes in the class II region that control class I expression. Hence, we studied fresh peripheral blood mononuclear cells (PBMCs) and newly produced Epstein-Barr virus (EBV)-transformed cell lines from multiple sclerosis patients for the class I defect. Unseparated PBMCs, as well as T cells, B cells, and macrophages from multiple sclerosis patients had a decrease in the amount of conformationally correct peptide-filled HLA class I molecules on the cell surface compared with matched controls detectable by flow cytometry. To demonstrate the independence of this defect from exogenous serum factors, newly produced EBV-transformed cell lines from B cells of patients with multiple sclerosis maintained the defect. In addition, DR2 +/+, +/-, and -/- EBV-transformed B cells from these patients similarly demonstrated the self-antigen presentation defect. Analysis of a set of discordant multiple sclerosis twins revealed the class I defect was exclusively found on the affected twin lymphocytes, suggesting a role of this class I complex in disease expression. These data indicate that multiple sclerosis patients have abnormal presentation of self-antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

Gene Expression↗
PubMed1995

Tap-1 and Tap-2 gene therapy selectively restores conformationally dependent HLA Class I expression in type I diabetic cells.

Genetic susceptibility to many autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM) is statistically linked to the HLA class II region of chromosome 6. However, a distinguishing feature of patients with HLA class II-linked autoimmune disease is an abnormally low density of conformationally correct, self-peptide filled HLA class I molecules on the lymphocyte cell surface. The transporters associated with antigen processing (Tap-1 and Tap-2) are essential for normal class I expression and presentation of intracellular peptides, and these genes are located within the HLA class II region. The aims of this project were to determine if Tap genes could be implicated in the defective class I expression associated with IDDM by using a novel Epstein-Barr virus (EBV)-mediated gene transfer system to introduce a cloned, normal Tap-2 or Tap-1 gene into B cell lines from normal and IDDM patients and analyzing the effect on conformationally dependent class I expression. The results show that Tap-2 gene transfer in B cells from 40% of randomly selected IDDM patients increased expression of conformationally correct, cell-surface class I molecules to levels comparable with similarly treated B cells from normal control individuals. B cells from another 40% of IDDM patients responded to Tap-1 gene transfer. These effects were specific because B cells from normal individuals did not respond to Tap-1 or Tap-2 gene transfer with increased class I expression, and B cells from IDDM patients responding to Tap-2 gene transfer did not respond to Tap-1 gene transfer and vice versa. Thus, these complementation studies identify distinct, non-overlapping subsets of IDDM patients whose class I defect in B cells can be reversed by Tap-1 or Tap-2 gene transfer. The increase in class I expression induced by Tap gene transfer is associated with a reduction in the number of peptide-empty class I molecules as demonstrated by the response to exogenous peptide loading. Furthermore, the increase in self-peptide filled class I molecules induced by Tap gene transfer into B cells from IDDM patients is associated with restored antigen presentation to autologous T cells. These studies conclude that Tap gene dysfunctions may contribute to the defect in class I phenotype and antigen presentation demonstrated by IDDM patients. Defective presentation of self-peptides by antigen presenting cells can lead to the failed T cell education and tolerance to self antigens evident in IDDM. These studies functionally identify HLA class II region genes that contribute to an immunologic defect in IDDM.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Elimination of self-peptide major histocompatibility complex class I reactivity in NOD and beta 2-microglobulin-negative mice.

Nonobese diabetic (NOD) mice and beta 2-microglobulin-gene-ablated mice (beta 2M -/-) show impaired presentation of major histocompatibility complex (MHC) class I and self-peptides, structures now recognized as critical for T-cell education to endogenous peptides. The naturally occurring NOD class I presentation abnormality appears to be attributable to, in part, a quantitative defect in the production of Tap-1 mRNA; Tap-1 with Tap-2 normally functions as a transporter for stable self-peptide and class I assembly. This study attempts to reverse NOD and beta 2-M -/- mouse autoreactivity by introduced or reestablished syngeneic class I presentation. Introduction of MHC class I and self-peptides on syngeneic MHC class I-matched cells specifically prevented diabetes in NOD mice and eliminated in vitro class I-directed T-cell autoreactivity in NOD and beta 2M -/- mice. Reestablishment of endogenous class I and self-peptide presentation in NOD mice was achieved with two well-described cures for the NOD mouse, complete Freund's adjuvant and mouse hepatitis virus. Both treatments induced Tap-1 mRNA, reestablished class I presentation of endogenous antigens, and eliminated in vitro and in vivo T-cell autoreactivity of self-peptides in the class I groove. These results substantiate a therapeutic role of self-peptide complexed with class I for T-cell education and suggest that some well-described NOD treatments may work, in part, through reestablishment of tolerance through class I and self-peptide.

Aging↗
PubMed1993

MHC class I and autoimmune diabetes.

The cause of failed self tolerance, resulting in autoimmunity is unknown, although genetic linkage to genes within the MHC class II region have been well described. We present evidence that failed self tolerance in autoimmune diabetes appears to be secondary to an antigen presenting cell defect; the diabetic antigen presenting cells fail to deliver fragments of endogenous antigens to the cell surface in the groove of MHC class I. In the diabetic NOD mouse model, this correlates with a rare allele at the Tap-1 locus, a gene that controls proper MHC class I assembly by providing fragments of endogenous peptides into the endoplasmic reticulum. We propose that MHC class I presentation of self peptides may represent a normal pathway for tolerance induction and interruption of this important class I function from any cause, including the MHC class II-linked Tap-1 and Tap-2 genes, which may result in autoreactivity.

Animals↗
PubMed1993

Defective major histocompatibility complex class I expression on lymphoid cells in autoimmunity.

Lymphocytes from patients with insulin-dependent diabetes mellitus (IDDM), a chronic autoimmune disease, have recently been shown to have decreased surface expression of MHC class I antigens. Since IDDM and other autoimmune diseases share a strong genetic association with MHC class II genes, which may in turn be linked to genes that affect MHC class I expression, we studied other autoimmune diseases to determine whether MHC class I expression is abnormal. Fresh PBLs were isolated from patients with IDDM, Hashimoto's thyroiditis, Graves' disease, systemic lupus erythematosis, rheumatoid arthritis, and Sjogren's syndrome. Nondiabetic and non-insulin-dependent diabetes mellitus patients served as controls. MHC class I expression was measured with a conformationally dependent monoclonal antibody, W6/32. Freshly prepared PBLs from the autoimmune diseases studied and the corresponding fresh EBV-transformed B cell lines had decreased MHC class I expression compared with PBLs from normal volunteers and non-insulin-dependent (nonautoimmune) diabetic patients. Only 3 of more than 180 donors without IDDM or other clinically recognized autoimmune disease had persistently decreased MHC class I expression; one patient was treated with immunosuppressive drugs, and subsequent screening of the other two patients revealed high titers of autoantibodies, revealing clinically occult autoimmunity. Patients with nonautoimmune inflammation (osteomyelitis or tuberculosis) had normal MHC class I expression. Autoimmune diseases are characterized by decreased expression of MHC class I on lymphocytes. MHC class I expression may be necessary for self-tolerance, and abnormalities in such expression may lead to autoimmunity.

Adult↗
PubMed1993

Faulty major histocompatibility complex class II I-E expression is associated with autoimmunity in diverse strains of mice. Autoantibodies, insulitis, and sialadenitis.

Many regions and loci of the murine genome contribute to the pancreatic and salivary gland autoimmunity observed in the diabetic NOD mouse. Examination of the major histocompatibility complex region of the NOD mouse has revealed a defect in the expression of the major histocompatibility complex class II gene, I-E. To determine the isolated role of faulty I-E expression in abnormal self-recognition, we examined six commonly used inbred strains of mice on diverse genetic backgrounds that also do not express I-E, i.e., C57BL/10, SJL, ACA, DBA/1, NOD, and 129. Autoimmunity was assessed by the presence of inflammatory cell infiltrates (0,+/-,+,++, , +) within and among the pancreatic islets and salivary glands, and autoantibodies to self determinants. At 6 mo of age, inflammatory infiltrates in the pancreas (0, 3 mice; +/-, 3 mice; +, 7 mice; ++, 6 mice; , 1 mouse; +, 5 mice) and/or salivary glands (0, 0 mice; +/-, 3 mice; +, 1 mouse; ++, 4 mice; , 6 mice; +, 10 mice) were detected as well as autoantibodies in all 24 mice of all I-E- mouse strains on diverse genetic backgrounds. This indicates that defective expression of this single locus, in isolation, is sufficient for the spontaneous development of autoreactivity. In contrast, the simultaneous examination of 19 I-E+ mice on five commonly used inbred strains of mice (BALB/c, C67/KsJ, B10.BR, B10.A [2R], and B10.A [5R]) demonstrated no signs of humoral or cellular autoimmunity with target gland destruction or lymphocytic invasion. Our data suggest that many commonly used inbred strains of mice represent models of autoimmunity attributable to this single defective gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Xenotransplantation of canine, bovine, and porcine islets in diabetic rats without immunosuppression.

Permselective acrylic membranes were employed to prevent immune rejection of discordant islet xenografts isolated from various large animals. Canine, porcine, and bovine islets were seeded into tubular diffusion chambers and transplanted into the peritoneum of 27 nonimmunosuppressed streptozotocin-induced diabetic Lewis rats. Six recipients received islet grafts from bovine calves, 7 received grafts from pigs, and 14 received grafts from dogs. Four of the latter were removed at 1 month. In the control group of 10 diabetic rats, 4 received nonencapsulated canine islets, 3 received nonencapsulated bovine islets, and 3 received nonencapsulated porcine islets. Recipients of encapsulated islets promptly dropped from a pretransplantation plasma glucose level of 487 +/- 36 (mean +/- SEM) to 84 +/- 2 (canine), 81 +/- 4 (bovine), and 81 +/- 3 mg/dl (porcine) during the first week. All of the animals sustained these levels for at least 1 month. One rat spontaneously reverted to diabetes at 54 days posttransplantation; 4 other rats became hyperglycemic (glucose, greater than 600 mg/dl) after membrane removal on day 30. The remaining 22 rats maintained fasting euglycemia for greater than 10 weeks. In contrast, rats that received nonencapsulated islets became hyperglycemic in less than 7 days. Intravenous glucose tolerance test K values (decline in glucose levels, %/min) at 1 month for the canine and bovine encapsulated islet transplant group were 3.5 +/- 0.3 and 3.3 +/- 0.1 compared with 3.3 +/- 0.1 (P = 0.63) and 0.91 +/- 0.1 (P less than 0.0001) for normal (n = 4) and diabetic (n = 4) control groups. Morphologic studies of long-term functioning grafts (30-130 days) revealed well-preserved alpha, beta, and delta cells, with varying degrees of granulation. These results demonstrate that immune isolation of islet tissue using permselective artificial membranes can protect discordant islet xenografts from immune rejection in the absence of any immunosuppressive drugs.

Analysis of Variance↗
PubMed1989

Sheep erythrocyte rosetting induces multiple alterations in T lymphocyte function: inhibition of T cell receptor activity and stimulation of T11/CD2.

When T lymphocytes from human blood or lymphoid organs are prepared by the sheep red blood cell (SRBC) rosetting procedure, glycoproteins of the SRBC membrane interact intimately with the CD2 (T11) molecule on the T cell surface. We now show that rosette formation has measurable short- and long-term effects upon the T cells. First, for a period of 24-48 hr after rosetting, the signal transducing and activation functions of the T3/Ti T cell antigen receptor complex is paralyzed for anti-T3-induced calcium mobilization, with a concomitant decrease in proliferative response to mitogens or stimulatory anti-T3 antibodies. Calcium mobilization through the alternate pathway of T cell activation, the T11/CD2 SRBC receptor, was also inhibited by rosetting. Second, rosetting appears to confer a partial stimulatory signal through the T11/CD2 pathway. Thus, 72 hr or more after rosetting, there was increased expression of the T11(3) activation epitope, and rosetted T cells were stimulated to proliferate in the presence of anti-T11(3) antibodies alone. These results provide further details on the effects of SRBC-T cell interactions, with important methodological implications. Moreover, they suggest a hitherto unrecognized down-regulatory effect of engaging the CD2 molecule, and provide further evidence that the T cell receptor is functionally interconnected to the CD2 activation pathway.

Animals↗