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Biomedical subjects

H S Luthra

Publications and source records attributed to H S Luthra.

At least 37 records · Page 2Linked to original sources
PubMed1996

H2-A polymorphism contributes to H2-Ebeta-mediated protection in collagen-induced arthritis.

Collagen-induced arthritis (CIA) is an animal model of auto-immune inflammatory polyarthritis which has features similar to rheumatoid arthritis (RA). Much like RA, susceptibility to mouse CIA is influenced by the major histocompatibility complex (MHC) and is restricted to the H2 haplotypes q and r. In previous experiments, we have found that the introduction of an H2-Ebd transgene in H2-Aq CIA-susceptible mice was able to protect these mice against disease development. More recently, we have proposed that the polymorphism of the first domain of the Ebeta molecule modulates this protection, and that the presentation of a peptide from the third hypervariable region of the Ebeta chain by the H2-Aq molecule plays an important role in this mechanism. In the present report, we investigated whether the H2-E-mediated protection is H2-Aq-specific and whether the source of collagen has any influence. While the source of collagen had no effect on the protection, our results showed that the H2-E molecule failed to protect B10.RIII (H2(r)) mice against CIA. Further, the H2 haplotype r exerted a negative effect on the Ebetad-mediated protection in H2-Aq-restricted disease. Our results provide additional proof that self-MHC-derived peptides, such as Ebeta peptides, may play an important role in the T-cell repertoire education and/or modulation of the T-cell response in the periphery.

Amino Acid Sequence↗
PubMed1995

Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin: a model of human spondyloarthropathies.

Human class I major histocompatibility complex allele HLA-B27 is associated with a group of human diseases called "spondyloarthropathies." Studies on transgenic rats expressing HLA-B27 and human beta 2-microglobulin have confirmed the role of HLA-B27 in disease pathogenesis. Here we report spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin (B27+ beta 2m-/-). In the absence of beta 2-microglobulin, B27+ beta 2m-/- animals do not express the HLA-B27 transgene on the cell surface and have a very low level of CD8+ T cells. Most of the B27+ beta 2m-/- male mice showed nail changes, hair loss, and swelling in paws, which leads to ankylosis. The symptoms occur only after the B27+ beta 2m-/- mice are transferred from the specific pathogen-free mouse colony. These results suggest that aberrant assembly, transport, and expression of the HLA-B27 molecule may predispose an individual for development of the disease when exposed to an appropriate environmental trigger.

Animals↗
PubMed1995

Oral administration of an immunodominant human collagen peptide modulates collagen-induced arthritis.

Human type II collagen (HuCII) may be one of the autoantigens involved in human rheumatoid arthritis (RA). By using over-lapping peptides, we have previously described an immunodominant region (HuCII.250-270) on HuCII. In the present study, this 21-mer HuCII.250-270 peptide was used as tolerogen, and its effect on both early and effector phase of collagen-induced arthritis (CIA) was examined. Upon immunization with HuCII-derived peptide 250-270, HuCII.250-270-tolerized mice showed diminished T cell proliferation that was mediated by Th1 cytokine, IL-2. More interestingly, oral tolerance with HuCII.250-270 peptide diminishes primarily a Th1 type of immune response. Arthritis severity was reduced markedly in mice orally tolerized with HuCII.250-270 peptide both at early and effector phases. Suppression of CIA at the effector phase by oral administration of HuCII peptide suggests a potential immunotherapeutic use of collagen II peptide in the treatment of human RA.

Administration, Oral↗
PubMed1995

Polymorphism of the MHC class II Eb gene determines the protection against collagen-induced arthritis.

Collagen-induced arthritis (CIA) is an animal model of auto immune polyarthritis, sharing similarities with rheumatoid arthritis (RA). Paradoxally, susceptibility to mouse CIA is controlled by the H2A loci (DQ homologous) while RA is linked to HLA.DR genes (H2E homologous). We recently showed that the E beta d molecule prevents CIA development in susceptible H2q mice. We addressed the question of whether H2Eb polymorphism will influence CIA incidence as HLA.DRB1 polymorphism does in RA. In F1 mice, only H2Ebd and H2Ebs molecules showed protection. Using recombinant B10.RDD (Ebd/b) mice, we found that CIA protection was mediated by the first domain of the E beta d molecule. Using peptides covering the third hypervariable region of the E beta chain, we found a perfect correlation between presentation of E beta peptides by the H2Aq molecule and protection on CIA. Therefore, the mechanism by which H2Eb protects against CIA seems to rely on the affinity of E beta peptides for the H2Aq molecule.

Amino Acid Sequence↗
PubMed1995

Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study.

PURPOSE: To evaluate the relationship between use of methotrexate in rheumatoid arthritis patients and development of hematologic malignancies. PATIENTS AND METHODS: We retrospectively analyzed all patients registered at the Mayo Clinic from 1976 through 1992 with rheumatoid arthritis (n = 16,263) cross-indexed with patients registered during the same period with a hematologic malignancy (n = 21,270). Adult patients were selected who had rheumatoid arthritis, were treated with a disease-modifying antirheumatic drug, and subsequently developed a hematologic malignancy. RESULTS: Thirty-nine patients met the selection criteria. Twelve of them had been given methotrexate. The characteristics of those who received methotrexate, including the type of hematologic malignancy, did not differ from those of patients who received other disease-modifying antirheumatic drugs. CONCLUSIONS: Hematologic malignancies are uncommon in patients with rheumatoid arthritis treated with disease-modifying antirheumatic drugs, including methotrexate. There does not appear to be a relationship between the peak or cumulative dose or the duration of methotrexate therapy and the subsequent development of hematologic malignancy. The histologic types of hematologic malignancy seen in the methotrexate-treated patients did not differ from those of patients treated with other disease-modifying antirheumatic drugs.

Adult↗
PubMed1995

Expression of an ovalbumin-specific V beta 8.2 TCR transgene inhibits collagen arthritis in B10.Q mice.

Previous studies have illustrated the importance of T cells bearing alpha beta TCRs in the induction and development of collagen induced arthritis (CIA) in mice. However, the scope of TCR usage in CIA has yet to be clearly defined. Given the inherent diversity of the TCR repertoire, the relative flexibility of the arthritogenic TCR repertoire specific for type II collagen (CII) is not clear. Therefore, we chose to examine the influence of a highly skewed TCR repertoire on CIA. Arthritis susceptible B10.Q (H-2q) mice were mated with C57L (H-2b) animals expressing an ovalbumin-specific V beta 8.2 TCR transgene (Tg) and Tg+ offspring were further backcrossed to B10.Q. Homozygous H-2q/q, V beta 8.2 Tg+ mice displayed a high level of V beta 8.2+ T cells in peripheral blood. However, expression of some endogenous V beta TCR, such as V beta 14, was still detected. Upon immunization with bovine CII in adjuvant, V beta 8.2 Tg+ mice were highly resistant to CIA when compared with Tg- littermates. Analysis of sera demonstrated a marked reduction in antibody specific for homologous mouse CII as well as heterologous bovine CII in Tg+ animals. Interestingly, V beta 8.2 Tg+ mice still mounted good antibody responses following immunization with human thyroglobulin, indicating that the skewed TCR repertoire affected anti-CII but not antithyroglobulin responses. Thus, our findings show that constraints placed on the TCR repertoire inhibit pathogenic responses against CII and suggest that in H-2q mice the arthritogenic TCR repertoire bears only limited flexibility.

Animals↗
PubMed1995

Identification of a cyanogen bromide fragment of porcine type II collagen capable of modulating collagen arthritis in B10.RIII (H-2r) mice.

Previous studies directed towards identifying epitopes on type II collagen (CII) important in collagen induced arthritis (CIA) in mice have focused primarily on responses mounted in susceptible H-2q strains. However, the nature of T and B cell responses against CII in susceptible H-2r strains remains ill-defined. In an effort to identify regions on CII important in CIA in H-2r mice, we examined the cellular and humoral response of susceptible B10.RIII (H-2r) mice against cyanogen bromide (CB)-cleaved fragments of porcine CII. Following immunization with native porcine CII, LNC from B10.RIII mice mounted proliferative responses predominantly to peptide CB10, while negligible proliferation was detected against fragment CB9, 7, CB8, CB11 or CB12. In contrast, sera from arthritic B10.RIII mice displayed a heterogeneous pattern of reactivity against porcine CII, with strong antibody binding measured against the major fragments CB11, CB8 and CB10. To determine the in vivo significance of the dominant cellular response to CB10, B10.RIII mice received an i.v. injection of soluble CB10 seven days before immunization with native porcine CII. Mice pretreated with CB10 were highly resistant to CIA compared to control animals. Interestingly, B10.RIII mice pretreated with fragment CB11, a region of CII implicated in H-2q restricted CIA, remained susceptible to arthritis induction. Collectively, our findings indicate that the CB10 region of porcine C11 bears determinants which may be important in the induction and/or regulation of CIA in the H-2r haplotype.

Adjuvants, Immunologic↗
PubMed1995

Altered development of collagen induced arthritis in T cell receptor V beta congenic B10.RIII mice.

Analysis of the mouse T cell receptor (TCR) V beta genome has revealed the existence of two distinct genotypes which bear deletions of certain V beta genes. Mice bearing the V beta a genotype lack approximately 50% of the V beta genome while V beta c mice lack 70% of the known V beta genes. Studies of the experimental model collagen induced arthritis (CIA) have indirectly suggested that the presence of truncated V beta genotypes may influence susceptibility to this autoimmune disease. In order to confirm the influence of V beta a and V beta c genotypes on CIA, we derived mice congenic for the known V beta haplotypes in the CIA susceptible B10.RIII (H-2r) background. Flow cytometric analysis of splenic lymphocytes revealed normal T cell levels in both B10.RIII-V beta congenic lines. Expectedly, a generalized increase in the expression of some non-deleted V beta genes was detected. In addition, the mice were immunized with porcine type II collagen and monitored for CIA. B10.RIII-V beta a mice showed little difference in arthritis incidence or severity versus B10.RIII, but a significant delay in the onset of CIA was seen. In contrast, B10.RIII-V beta c mice showed a marked decrease in arthritis incidence versus B10.RIII and the severity of CIA in arthritic mice was also significantly lower (p < 0.01). Thus, in the B10.RIII strain, the presence of truncated TCR V beta genotypes alters the development of CIA. These findings may shed light on the influence of TCR genotypes in the induction and development of human rheumatoid arthritis.

Animals↗
PubMed1994

Protective role of major histocompatibility complex class II Ebd transgene on collagen-induced arthritis.

Collagen-induced arthritis (CIA) is an animal model of autoimmune inflammatory polyarthritis that has features similar to rheumatoid arthritis (RA). Much like RA, susceptibility to mouse CIA is influenced by the major histocompatibility complex (MHC), H-2, and restricted to the H-2q and H-2r haplotypes. Whereas the role of the H-2A molecule in susceptibility to CIA is well established, little is known about the role of H-2E molecule in the disease. In this study, we analyzed the effect of a transgenic E beta d molecule on CIA susceptibility in a recombinant mouse B10.RQB3, which expresses the CIA susceptible Aq genes and an Eak gene, but does not produce an E molecule since Ebq is nonfunctional. In the presence of an Ebd transgene, a viable E molecule is generated. Whereas B10.RQB3 were susceptible to CIA, B10.RQB3-E beta d+ showed a dramatic reduction in the incidence of arthritis as well as a decrease in the level of anti-mouse and anti-bovine CII antibodies in their serum. No clear cut differences in the expression of T cell receptor (TCR) V beta was observed between E beta d+ and E beta d- transgenic mice. Mechanisms underlying the protective effect of E beta d transgenic molecule on CIA may shed light on how HLA-DR molecules influence human RA.

Animals↗
PubMed1994

Collagen-induced arthritis and TCRs in SWR and B10.Q mice expressing an Ek alpha transgene.

B10.Ek alpha transgenic mice were mated with H2-E B10.Q and SWR mice. F1 and F1 x parental strain backcross progeny were tested for arthritis and autoimmune reactivity to mouse type II collagen (MII) after immunization with bovine, chick, deer, or human type II collagen. The results were correlated with the H-2 haplotype (b/q vs q/q) and the TCR V beta profile of peripheral blood T cells in each mouse. Hybrid progeny expressed TCR profiles different from either parent because of the TCR V beta genomic deletions of SWR mice (V beta a), the wild-type TCR allele of C57Bl/10 (B10) mice (V beta b), and the intrathymic negative selection processes resulting from cell surface expression of Ek alpha-A q beta or Eb beta-Ek alpha, together with the integrated retroviral genes Mtv-9 originating in B10 mice and Mtv-7 (Mls-1a) from SWR mice. (B10.Ek alpha x SWR)F1 mice developed higher IgG anti-MII Ab titers, but much milder arthritis than (B10.E x B10.Q)F1 mice. Expression of Ek alpha did not change the level of IgG anti-MII Ab nor the degree of susceptibility to collagen-induced arthritis (CIA) in the H-2q/q and H-2b/q progeny of (B10.Ek alpha x B10.Q)F1 x B10.Q matings, indicating that the Mtv-9-reactive, TCR V beta 5+, and V beta 11+ T cells are not critical to CIA. Among bovine type II collagen-immunized (B10.Ek alpha x SWR)F1 x SWR backcross mice: 1) arthritis severity is associated with the presence of V beta b (p < or = 0.01) and expression of Ek alpha (p < or = 0.05), but not with the MHC haplotype (b/q vs q/q); 2) regression analysis showed a significant association (R = 0.99) between IgG anti-MII Ab titers and the level of Mtv-7-reactive V beta 6+ T cells that was detectable in the IgG1, but not the IgG2a subclass. The data prompt the speculation that Mtv-7-reactive V beta 6+ (or V beta 7+) T cells in (B10.EK alpha x SWR)F1 x SWR mice express Th2-type properties, and thus contribute to the combination of mild arthritis but high anti-MII Ab titers that characterize mice of SWR heritage.

Animals↗
PubMed1994

Collagen-induced arthritis in T cell receptor V beta congenic B10.Q mice.

B10.Q (H-2q) mice congenic for the truncated T cell receptor (TCR) V beta a and V beta c haplotypes were derived to examine the influence of TCR V beta genomic deletions in murine collagen-induced arthritis (CIA). Previous studies using gene complementation and segregation analyses suggested that in SWR (H-2q) mice, possession of the V beta a gene deletion results in CIA resistance. However, other studies have suggested alternative hypotheses. Thus, analysis of TCR V beta congenic mice allows for direct examination of V beta genotypes in CIA control. After immunization with bovine type II collagen, B10.Q-V beta a mice showed no difference in arthritis susceptibility, onset, or severity when compared with prototype B10.Q mice. In contrast, B10.Q-V beta c mice, which lack the V beta 6, 15, 17, and 19 families in addition to the V beta a deletion, were highly resistant to CIA. In vivo depletion of V beta 6+ T cells in B10.Q-V beta a mice significantly delayed arthritis onset suggesting that, among those V beta genes present in V beta a but absent in V beta c, V beta 6+ T cells contribute to arthritogenesis. Our findings show that, in B10.Q-V beta congenic mice, while the V beta a genotype does not prevent CIA, the highly truncated V beta c genotype renders B10.Q mice resistant to CIA. Thus, deletions within the V beta TCR genome can indeed influence CIA and suggests that the TCR repertoire displays only marginal flexibility in response to arthritogenic stimuli.

Animals↗
PubMed1994

Iliocaval complications of retroperitoneal fibrosis.

BACKGROUND: Retroperitoneal fibrosis can compress ureters, nerves, and blood vessels in the abdomen. However, clinically significant large-vein obstruction secondary to this process is rare. METHODS: Three hundred forty patients with retroperitoneal fibrosis were treated at our institution between 1976 and 1993. The clinical data from seven of these patients, who were treated for iliocaval complications of retroperitoneal fibrosis, were reviewed. RESULTS: Six patients had signs and symptoms of chronic obstruction, and one patient presented with acute iliocaval thrombosis and underwent attempt at venous thrombectomy in the referring hospital. All patients exhibited extremity edema and three had venous claudication. Iliocaval occlusion was confirmed in all patients by venography, computed tomography, or magnetic resonance imaging. The obstructive process involved the iliocaval tree (four patients), the inferior vena cava alone (two patients), and the iliac vein alone (one patient). Five patients were managed conservatively with leg elevation, compression stockings, and anticoagulation. Two patients received prednisone. One patient underwent an iliocaval bypass from the external iliac vein to the juxtarenal cava using a ringed polytetrafluoroethylene graft with a femoral arteriovenous fistula. A second patient with an isolated left common iliac vein obstruction underwent a left-to-right femorofemoral saphenous vein bypass. Four patients treated conservatively continued to have extremity edema. The two patients managed surgically remain asymptomatic from venous insufficiency, with patent grafts at 25 and 12 months after surgery, respectively. CONCLUSION: Iliocaval obstruction is an unusual complication of retroperitoneal fibrosis. Although most cases can be managed conservatively, reconstruction is an option for patients who have failed medical treatment and are symptomatic secondary to chronic venous obstruction. Lifelong anticoagulation should be considered for all patients with progressive iliocaval obstruction secondary to retroperitoneal fibrosis.

Acute Disease↗
PubMed1993

Prevention of collagen induced arthritis in mice by deletion of T cell receptor V beta 8 bearing T cells with monoclonal antibodies.

Collagen induced arthritis (CIA) is an animal model of inflammatory polyarthritis. Immunotherapy with the monoclonal antibody F23.1, which deletes V beta 8 bearing T cells, significantly decreased the incidence of CIA in mice. Treatment with the monoclonal antibody 466B5, to delete V beta 6 bearing T cells in combination with F23.1 was no more effective than F23.1 alone and the CIA incidence in 466B5 treated animals was not significantly different from controls. Thus, the V beta 8 family of T cell receptor is expressed on self-reactive T cells in the CIA model of B10.RIII mice injected with porcine type II collagen.

Animals↗
PubMed1993

T-cell receptors and collagen induced arthritis in H-2r mice.

Mouse strains B10, B10.RIII, RIIIS/J and the F1 and backcross progeny arising from them were tested for susceptibility to porcine type II collagen-induced arthritis (PII-CIA). The clinically severe arthritis of rapid onset that is characteristic of PII-immunized B10.RIII mice developed predominantly in hybrid offspring that had inherited at least one copy of wild type T cell receptor (TCR) genes (V beta b genotype) from the B10 or B10.RIII parent. The results indicate that, in the development of PII-CIA, mice expressing the H-2r/r haplotype preferentially utilize TCR V beta genes that are normally encoded within the TCR V beta genomic deletion region of RIIIS mice (V beta c). After aggressive immunization with PII, the use of alternative TCR V beta genes, encoded outside of the RIIIS deletion region, produced a high IgG antibody response that was cross-reactive with mouse type II collagen (MII) and equivalent to that of B10.RIII mice, but only a very mild, late onset arthritis of 56% (27/48) incidence in RIIIS male mice and 28% (10/35) incidence in RIIIS female mice. In comparison, B10.RIII mice routinely developed early onset of PII-CIA of significantly higher incidence (100%; p < 0.005) and four-fold greater severity, even after milder immunization protocols. The data are compatible with the proposal that the clinically weak CIA response of RIIIs mice may be primarily antibody driven while the severe CIA of B10.RIII mice reflects the added inflammatory effects of collagen-reactive effector-T cells in the joint.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Prevention of collagen induced arthritis in mice by treatment with an antibody directed against the T cell receptor alpha beta framework.

Collagen induced arthritis (CIA) is an animal model of inflammatory polyarthritis. Type II collagen is the major matrix protein of hyaline cartilage. Susceptibility to CIA is linked to the Major Histocompatibility Complex Class II genes but the presence of T cells expressing specific variable beta (V beta) chain of their T cell receptor (TCR) is also required. Pretreatment with the monoclonal antibody H57-597 directed against the TCR alpha beta framework prevented the onset of arthritis in the majority of animals. The depletion of the T cell population did not lead to any apparent health problems. These experiments demonstrate the important role of the alpha/beta T cell and its receptors in the CIA model. Further, anti-TCR alpha beta antibodies may be of value in the therapy of autoreactive disorders.

Animals↗
PubMed1991

Role of Mls-1 locus and clonal deletion of T cells in susceptibility to collagen-induced arthritis in mice.

The role of T cell-mediated and humoral immunity to type II collagen has been well documented in collagen-induced arthritis (CIA). Previous work from our laboratory has indicated that genomic deletions of TCR V beta genes may play a role in CIA resistance in mice. This indicated a selectivity of TCR usage by autoreactive T cells in CIA in mice. Certain strains of mice, although having a normal genomic V beta TCR repertoire, can show clonal deletion of peripheral T cells that bear specific V beta gene products in their TCR. These clonally deleted T cells are reactive with self-Ag such as minor lymphocyte stimulation (Mls) Ag. An Mls-congenic strain, BALB.D2.Mlsa, which differs only at the Mls-1 a locus from BALB/c (Mls-1b), was used to examine the effect of clonal deletion of Mls-1a-reactive T cells in CIA. These two strains were crossed to three CIA-susceptible strains, B10.RIII (H-2r, Mls-1b), DBA/1 (H-2q, Mls-1a), and B10.Q (H-2q, Mls-1b), and the crosses were injected with type II collagen. A significantly decreased incidence of arthritis was observed in the (BALB.D2.Mlsa x B10.Q)F1 hybrids, compared with (BALB/c x B10.Q)F1 hybrids, upon immunization with chick type II collagen. The BALB.D2.Mlsa cross mice also had significantly lower levels of antimouse collagen antibodies. Flow cytometric analysis confirmed the clonal deletion of Mls-1a-reactive V beta 8.1, V beta 6, V beta 7, and V beta 9 subsets in the (BALB.D2.Mlsa x B10.Q)F1 hybrids. The study of H-2q/d mice in (BALB.D2.Mlsa x B10.Q) x B10.Q back-crosses demonstrated a significant correlation between CIA resistance and Mls-1a locus. On the other hand, B10.RIII crosses showed only a modest decrease in CIA incidence in the presence of Mls-1a. As expected, all the DBA/1 crosses had an equal incidence of CIA, which was somewhat less than that seen in DBA/1 mice themselves. These studies point out that the Mls-1a locus could play a role in decreasing CIA incidence by clonal deletion of T cells bearing specific V beta TCR, which may be involved in the pathogenesis of CIA. The influence of the clonal deletion of T cells on CIA, and hence the usage of specific V beta TCR by autoreactive anti-type II collagen T cells, however, depends not only on the source of the type II collagen and the MHC class II molecules involved but also on other background genes in mice.

Animals↗
PubMed1990

Susceptibility of HLA-B27 transgenic mice to Yersinia enterocolitica infection.

The majority of patients with reactive arthritis have the major histocompatibility complex class I gene HLA-B27. The development of arthritis in these patients often occurs following infection with one of several enteric bacteria, including Yersinia enterocolitica. In this study, transgenic mice expressing HLA-B27 and their negative full sibs were infected intravenously with Yersinia enterocolitica 0:8 WA in an attempt to develop an experimental model of reactive arthritis. To date, no reactive arthritis has been observed; however, a significantly higher incidence of paralysis was observed in the HLA-B27+ transgenic mice. Injection of 10(5) organisms induced hind limb paralysis in 8 out of 30 of the HLA-B27 transgenic mice (27%) and in only 1 of the 24 negative siblings (4%). Paralysis occurred in 14 out of 30 HLA-B27+ mice (47%) at a dose of 10(4) organisms. Only 2 of the 25 negative siblings (8%) were affected at this dose. Paraspinal abscesses were found in all of the paralyzed animals. At the 10(4) dose most of the HLA-B27+ mice (70%) succumbed to the disease within 4 weeks, while the mortality in their B27- full sibs was less than 10%. Thus, HLA-B27 transgenic mice have higher mortality and morbidity from infection with Y. enterocolitica 0:8 WA than corresponding HLA-B27- littermates.

Animals↗