Cyclosporine therapy for autoimmune disease.
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Arthritis, Rheumatoid↗
Biomedical subjects
C G Fathman
Publications and source records attributed to C G Fathman.
Presentation of antigen by mixed isotype class II molecules in normal H-2d mice.
A panel of DBA/2 T cell hybridomas specific for the sperm whale myoglobin epitope 110-121 was found to recognize antigen presented by the mixed isotype class II molecule E alpha dA beta d. The response was blocked by monoclonal antibodies specific for E alpha and A beta d chains; in addition, the hybridomas responded to antigen presented by L cells expressing E alpha A beta d molecules, and made no response with L cells expressing I-Ad or I-Ed molecules. Two more groups of hybridomas isolated from DBA/2 and B10.D2 mice immunized with myoglobin also recognized peptide 110-121 presented by E alpha d A beta d. Thus, although it is expressed at biochemically undetectable levels on spleen cells, the E alpha d A beta d molecule is an important presenting element in normal H-2d mice making a conventional immune response to a protein antigen. These results suggest that high levels of class II expression are not a prerequisite for T cell activation.
Animals↗
Inhibition of immune induction: the target of current transplantation tolerance strategies.
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Animals↗
Anti-CD4 monoclonal antibodies in therapy: creation of nonclassical tolerance in the adult.
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Adult↗
Immunotherapy of rheumatic diseases based on understanding genetic predisposition to the development of these diseases.
During the past two decades, investigators have made great inroads in understanding markers of genetic predisposition to the development of rheumatic diseases. An important question that must be addressed by investigators and clinicians is whether this knowledge will ultimately benefit patients, either through genetic counseling or predictions for beneficial therapeutic intervention. This article discusses various disease mechanisms and modes of immunotherapy such as anti-CD4, major histocompatibility complex blockade, and T-cell receptor-based and determinant-induced responsiveness.
CD4 Antigens↗
What a rheumatologist needs to know about T cell receptor structure and function.
By understanding normal immune response, it has been possible to develop therapeutic strategies toward the treatment of autoimmune disease. The association of autoimmune disease with the major histocompatibility complex (MHC) class II gene products suggests that the inductive events in which the putative autoantigen is presented on the surface of antigen presenting cells in the context of the MHC class II gene products and is recognized by CD4(+) helper or inducer T cells form an interesting target for immunotherapeutic intervention. By understanding the structure/function relationships of T cell receptors for antigen, it might be possible to develop novel immunotherapeutic strategies for the treatment of seropositive rheumatoid arthritis. Studies described below review recent progress in understanding the components of the ternary complex and suggest possible areas of immunotherapeutic intervention.
Animals↗
Genetic dissection of T cell receptor V beta gene requirements for spontaneous murine diabetes.
It has been demonstrated, in certain autoimmune disease models, that pathogenic T cells express antigen receptors of limited diversity. It has been suggested that the T cells responsible for the pathogenesis of type I diabetes mellitus might similarly demonstrate restricted T cell receptor (TCR) usage. Recently, attempts have been made to identify the V beta subset(s) that initiates and/or perpetuates the antiislet response in a mouse model of spontaneous autoimmune diabetes (non-obese diabetic [NOD] mice). In studies reported here, we have bred NOD mice to a mouse strain that congenitally lacks approximately one-half of the conventional TCR V beta alleles. Included in this deletion are TCR V beta gene products previously implicated as being involved in the pathogenesis of NOD disease. By studying second backcross-intercross animals, we were able to demonstrate that this deletion of TCR V beta gene segments did not prevent the development of insulitis or diabetes.
Animals↗
The T cell receptor repertoire influences V beta element usage in response to myoglobin.
T cell clones recognizing the sperm whale myoglobin (SpWMb) epitope 110-121 in association with H-2d major histocompatibility complex class II molecules display a very limited heterogeneity of T cell receptor (TCR) V beta usage in DBA/2 mice. All clones previously tested used the same V beta 8.2 gene segment and very restricted junctional regions. To investigate the significance of this observation in vivo, we immunized DBA/2 mice with the intact SpW Mb protein or peptide 110-121. Only the V beta 8+ T cells showed any significant response to the 110-121 epitope. The response to peptide 110-121 was then analyzed in mice which, either as a consequence of antibody depletion or through genetic deletion of TCR V beta genes, lacked V beta 8+ peripheral T cells. DBA/2 mice depleted of V beta 8+ T cells by antibody treatment responded poorly to the 110-121 peptide, and only at high antigen concentrations. In contrast, DBA/2V beta a mice (homozygous for a deletion of multiple V beta gene segments including the V beta 8 family) made a response at least as great as that made by DBA/2 mice, even though the DBA/2V beta a mice had a very restricted TCR V beta repertoire compared with DBA/2 mice. Mechanisms which might determine differences in the 110-121 specific response of DBA/2, DBA/2V beta a and F23.1-treated DBA/2 mice are discussed.
Animals↗
Anti-CD4 mediates clonal anergy during transplantation tolerance induction.
Depletion of CD4+ cells using anti-CD4 monoclonal antibodies leads to allograft tolerance. Here we show that anti-CD4-mediated tolerance to pancreatic islets of Langerhans transplanted from an A/J (IEk) donor to a diabetic C57B1/6 (B6) (IE-) recipient occurs in the absence of clonal deletion of the potentially IE-reactive V beta 11+ T cells. Instead, a state of clonal anergy is induced in both the CD4+V beta 11+ and CD8+V beta 11+ T cell subsets. This clonal anergy can be partially overcome in vitro by the addition of recombinant interleukin 2.
Animals↗
Genetic analysis of diabetes in the nonobese diabetic mouse. I. MHC and T cell receptor beta gene expression.
Backcross nonobese diabetic (NOD) ((NOD x SWr)F1 x NOD) mice (108 females and 105 males) were typed for MHC, TCR V beta, and monitored for 350 days for the onset of diabetes. The presence of "antipolar" antibodies in the sera and the occurrence of insulitis was examined in a proportion of these backcross mice. There was no difference in the incidence of diabetes in mice heterozygous for TCR V beta b/a vs those homozygous for TCR V beta b/b. Among the 17 diabetics (all female) detected in this backcross, 14/17 were H-2nod/nod but 3/17 were H-2nod/q. This supports a previous observation suggesting that the MHC-linked diabetogenic gene originally thought to be recessive may rather be dominant but have a low penetrance in the heterozygous state. Antipolar autoantibodies were found in both female and male backcross mice, and were similarly distributed in diabetic and nondiabetic mice. There appeared to be no correlation between the level of these auto-antibodies and development of diabetes. The incidence and severity of insulitis was linked to MHC but no influence of TCR genes on insulitis nor an association between insulitis and antipolar antibodies could be demonstrated in this study. Further analyses of H-2nod/nod intercross mice homozygous for TCR V beta a or TCR V beta b are currently underway.
Animals↗
Molecular analysis of the role of the HLA class II genes DRB1, DQA1, DQB1, and DPB1 in susceptibility to Lyme arthritis.
Using the polymerase chain reaction and sequence-specific oligonucleotide probes, we have determined the distribution of the alleles at the polymorphic class II loci, DRB1, DQA1, DQB1, and DPB1 in 25 patients with Lyme arthritis. Comparison of the frequencies of the DRB1 and DPB1 alleles in Lyme arthritis patients to the Centre d'Etude du Polymorphisme Humaine control panel revealed statistically significant differences between the two groups. An increase in DRB1*1301 is noted along with a unique distribution of the DR4 subtypes within the 9 DR4+ patients. In addition, an increase in the rate DPB1*1001 and the more common DPB1*0201 alleles is reported.
Disease Susceptibility↗
Anti-CD8 abrogates effect of anti-CD4-mediated islet allograft survival in rat model.
We studied the effects of anti-CD4 treatment of diabetic ACI rats on the induction of tolerance to allogeneic (Lewis) islet allografts. When given as a 4-day treatment regimen, OX38, a mouse anti-rat CD4 antibody, caused depletion of greater than 80% of CD4+ cells from the peripheral blood of treated rats. After induction of diabetes (a single high-dose bolus of streptozocin) and 3 days after the initiation of anti-CD4 immunotherapy, recipient ACI rats were transplanted with fully allogeneic (Lewis) islets of Langerhans via the portal circulation. These transplanted islets were capable of returning the anti-CD4-treated ACI recipients to normoglycemia, which was maintained indefinitely in the absence of further immunosuppression. In contrast, treatment of recipient rats with OX8, an anti-CD8 monoclonal antibody (MoAb), induced only a slight prolongation of graft survival (less than or equal to 30 days). Further characterization of the cellular requirements for the induction of long-term transplantation survival revealed that successful pretransplantation anti-CD4 therapy could be ablated by the coincident treatment of recipient rats with depleting levels of anti-CD8 MoAb. These data point to the necessity of a regulator CD8+ cell in the induction of anti-CD4-mediated transplantation survival in this rat model of islet transplantation.
Animals↗
T cell receptor-mediated negative selection of autoreactive T lymphocyte precursors occurs after commitment to the CD4 or CD8 lineages.
To identify the maturational stage(s) during which T cell receptor (TCR)-mediated positive and negative selection occurs, we followed the development of CD4+8- and CD4-8+ T cells from TCRlo CD4+8+ thymic blasts in the presence of different positive and negative selecting (major histocompatibility complex or Mls) elements. We describe novel lineage-committed transitional intermediates that are TCRmed CD4+8lo or TCRmed CD4lo8+, and that show evidence of having been positively selected. Furthermore, negative selection is not evident until after cells have attained one of the TCRmed transitional phenotypes. Accordingly, we propose that negative selection in normal mice occurs only after TCRlo CD4+8+ precursors have been positively selected into either the CD4 or CD8 lineage.
Animals↗
The presumptive CDR3 regions of both T cell receptor alpha and beta chains determine T cell specificity for myoglobin peptides.
The T cell receptor alpha/beta (TCR-alpha/beta) is encoded by variable (V), diversity (D), joining (J), and constant (C) segments assembled by recombination during thymocyte maturation to produce a heterodimer that imparts antigenic specificity to the T cell. Unlike immunoglobulins (Igs), which bind free antigen, the ligands of TCR-alpha/beta are cell surface complexes of intracellularly degraded antigens (i.e., peptides) bound to and presented by polymorphic products of the major histocompatibility complex (MHC). Therefore, antigen recognition by T cells is defined as MHC restricted. A model has been formulated based upon the similarity between TCR-alpha/beta V region and Ig Fab amino acid sequences, and the crystal structure of the MHC class I and Ig molecules. This model predicts that the complementarity determining regions (CDR) 1 and 2, composed of TCR V alpha and V beta segments, primarily contact residues of the MHC alpha helices, whereas V/J alpha and V/D/J beta junctional regions (the CDR3 equivalent) contact the peptide in the MHC binding groove. Because polymorphism in MHC proteins is limited relative to the enormous diversity of antigenic peptides, the TCR may have evolved to position the highly diverse junctional residues (CDR3), where they have maximal contact with antigen bound in the MHC peptide groove. Here, we demonstrate a definitive association between CDR3 sequences in both TCR alpha and beta chains, and differences in recognition of antigen fine specificity using a panel of I-Ed-restricted, myoglobin-reactive T cell clones. Acquisition of these data relied in part upon a modification of the polymerase chain reaction that uses a degenerate, consensus primer to amplify TCR alpha chains without foreknowledge of the V alpha segments they utilize.
Amino Acid Sequence↗
DRB1*LY10--a new DRB1 allele and its haplotypic association.
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Amino Acid Sequence↗
Shared molecular markers of genetic predisposition to seropositive rheumatoid arthritis.
Rheumatoid arthritis is associated with the human class II major histocompatibility complex antigens known as HLA-DR4. HLA-DR4 can be subdivided by cellular typing into five subtypes: Dw4, Dw10, Dw13, Dw14, and Dw15. By traditional serologic methods, 60-80% of rheumatoid arthritis patients type HLA-DR4 compared to approximately 20% of the general population. It has been demonstrated, using a panel of four alloreactive T-cell clones, each of which recognized HLA-DR4, Dw14 homozygous typing cells, that cells from all of a group of 23 rheumatoid arthritis patients could be recognized by one or more of these clones regardless of the patients' serologic typing. As the expressed polymorphism of the DR molecule is accounted for by the beta 1 gene, this gene was amplified, using the polymerase chain reaction, and sequenced. Seven patients whose cells were recognized by one of the DR4, DW14-specific T-cell clones, T431, were analyzed. All of these patients shared a common sequence in the third hypervariable region of the DR beta 1 chain gene. The sequence identified is the one normally associated with DR4, Dw14 and DR1. Patients and DR4-positive controls whose cells did not stimulate this clone did not share this sequence. These results suggest that this hypervariable region might be an important contribution to a restriction site for the putative causative agent(s) in rheumatoid arthritis.
Amino Acid Sequence↗
Induction of donor-specific unresponsiveness to cardiac allografts in rats by pretransplant anti-CD4 monoclonal antibody therapy.
In the present report a monoclonal antibody designated OX-38 directed against the rat CD4 molecule was tested for its ability to prolong the survival of heterotopic vascularized rat heart allografts transplanted across major histocompatibility barriers. Fluorescence-activated cell-sorter analysis showed that administration of OX-38 selectively depleted 80-95% of CD4+ cells from peripheral blood of treated rats. The immunosuppressive effects of OX-38 in vivo were verified by suppression of an antibody response against OX-38 itself as a heterologous protein immunogen. Recipient rats received OX-38 antibody as a single agent given in pretransplant regimens. Nine of 12 treated rats have maintained heterotopic abdominal heart allografts for greater than 175 days. Control rats that did not receive antibody therapy rejected their grafts within 14 days. Rats that maintained heart allografts for greater than 100 days accepted second donor strain hearts but rejected third-party heart grafts transplanted into the femoral space. Anti-CD4-induced allograft unresponsiveness persisted for at least 90 days following surgical removal of donor tissue and retransplantation of a second donor-matched heart. These results indicated that transient, pretransplant therapy with monoclonal antibodies directed against the CD4+ lymphocyte induced specific, long-lasting unresponsiveness to fully MHC-mismatched cardiac allografts in rats without additional immunosuppression.
Animals↗
A subset of memory CD4+ helper T lymphocytes identified by expression of Pgp-1.
The Pgp-1 glycoprotein (Ly-24 antigen) is acquired by mature murine T lymphocytes at the time of primary antigen stimulation Pgp-1 was previously shown to be a useful cell surface marker for distinguishing antigen-specific memory CD8+ T lymphocytes after immunization. Here we demonstrate that this observation extends to CD4+ T lymphocytes. Antigen-specific CD4+ T cells in mice immunized with sperm whale myoglobin or keyhole limpet hemocyanin were contained nearly exclusively in the minor Pgp-1+ subset.
Animals↗