Dendritic cells in the autoimmune insulitis in NOD mouse models of diabetes.
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Animals↗
Biomedical subjects
J D Katz
Publications and source records attributed to J D Katz.
Genetic control of diabetes progression.
Autoimmune diabetes in both the human and the nonobese diabetic mouse has elaborate genetics; in the latter case, the disease is influenced by at least 15-20 loci. We anticipated that the genetics would be simpler in the BDC2.5 T cell receptor transgenic mouse model of diabetes, wherein many T cells express a particular diabetogenic specificity. Initiation of insulitis in this model was the same on the two genetic backgrounds analyzed, but the kinetics and penetrance of diabetes were strikingly different, permitting us to focus on genetic influences during a defined window of disease progression. The differences correlated with variations in five genomic intervals, certain ones of which have been previously implicated in susceptibility to autoimmune disease. This reductionist approach indeed simplified the analysis of diabetes susceptibility loci.
Animals↗
T helper cell subsets in insulin-dependent diabetes.
It has been proposed that the development of insulin-dependent diabetes is controlled by the T helper 1 (TH1) versus TH2 phenotype of autoreactive TH cells: TH1 cells would promote diabetes, whereas TH2 cells would actually protect from disease. This proposition was tested by establishing cultures of TH1 and TH2 cells that express an identical diabetogenic T cell receptor and comparing their ability to initiate disease in neonatal nonobese diabetic mice. TH1-like cells actively promoted diabetes; TH2-like cells invaded the islets but did not provoke disease--neither did they provide substantial protection.
Animals↗
Benefit of late coronary reperfusion in patients with acute myocardial infarction and persistent ischemic chest pain.
The benefit of thrombolytic therapy given late after the onset of acute myocardial infarction (AMI) has been controversial because of low reperfusion rates and limited myocardial salvage. Persistent chest pain has been used as a criteria for late intervention, but there is little documentation to validate this practice. Clinical outcomes and myocardial salvage were evaluated in 74 patients with AMI and persistent chest pain who underwent late reperfusion (> 6 hours) with direct coronary angioplasty, and these were compared with outcomes in 460 patients with early reperfusion (< or = 6 hours). Patients with late reperfusion had a high infarct artery patency rate (96%), a low hospital mortality rate (5.4%), and a low incidence of reinfarction (1.4%) and recurrent ischemia that were similar to patients with early reperfusion. Patients with late reperfusion had surprisingly good recovery of left ventricular function with improvement in ejection fraction from 50% to 60% at follow-up angiography. Patients with late reperfusion had a greater incidence of collateral flow (45% vs 22%, p < 0.001) and a lower value of peak creatine kinase (1,357 vs 2,057 U/liter, p < 0.001) than patients with early reperfusion. This study emphasizes the importance of persistent chest pain as a marker of continued myocardial viability in patients who present late after AMI. These data suggest that the probable mechanism of continued viability is preserved flow to the infarct zone. Patients with AMI and persistent chest pain may benefit from reperfusion therapy beyond 6 to 12 hours.
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Following a diabetogenic T cell from genesis through pathogenesis.
Nonobese diabetic (NOD) mice spontaneously develop a disease very similar to type 1 diabetes in humans. We have generated a transgenic mouse strain carrying the rearranged T cell receptor genes from a diabetogenic T cell clone derived from a NOD mouse. Self-reactive T cells expressing the transgene-encoded specificity are not tolerized in these animals, resulting in rampant insulitis and eventually diabetes. Features of the disease process emphasize two so-called check-points, recognized previously in the NOD and human diseases but easily misinterpreted. Although NOD mice are protected from insulitis and diabetes by expression of the E molecule encoded in the major histocompatibility complex, the transgenics are not, permitting us to exclude some possible mechanisms of protection.
Amino Acid Sequence↗
A simple severity of disease index for systemic lupus erythematosus.
Although indices of activity for systemic lupus erythematosus have been developed and validated, a disease staging system requires the measurement of severity as well. We have constructed such a scale, the Lupus Severity of Disease Index (Lupus SDI). Accepted clinical, pathologic and physiologic classification schemes were employed to validate this index at two separate research institutions. The Lupus SDI allows homogenization of patient populations for the purposes of research and, possibly, for case mix adjustment.
Adolescent↗
Importance of a patent infarct-related artery for hospital and late survival after direct coronary angioplasty for acute myocardial infarction.
The importance of a patent infarct-related artery (IRA) for hospital and late survival was examined in 383 patients with acute myocardial infarction treated with direct coronary angioplasty. At hospital discharge, 317 of 348 patients (91%) had a patent IRA and mean follow-up left ventricular (LV) ejection fraction (EF) was 58%. Cardiac survival after hospital discharge at 1, 3 and 6 years was 99, 95 and 90%. Patency of the IRA was the most important determinant of hospital mortality: patent versus occluded IRA, 5 vs 39% mortality, p less than 0.001. Follow-up LVEF was the most important determinant of late cardiac mortality: follow-up LVEF greater than or equal to 45 versus less than 45%, 2 versus 24% mortality, p less than 0.001. Patency of the IRA was not a significant predictor of late cardiac mortality in the group as a whole: patent versus occluded IRA, 4.7 versus 6.5% mortality, p = 0.67. In the subgroup of patients with depressed initial LVEF less than 45%, patency was a significant predictor of late cardiac mortality: patent versus occluded IRA, 9.2 versus 40% mortality, p = 0.03. Patients with a patent IRA had better recovery of LV function than patients with an occluded IRA (follow-up LVEF 58.5 versus 47.6%, p less than 0.001). When late cardiac mortality was adjusted for differences in follow-up LVEF, patency was no longer a significant predictor of late mortality. Our results indicate patency of the IRA is the most important determinant of hospital survival, and LV function (measured after recovery) is the most important determinant of late cardiac survival.(ABSTRACT TRUNCATED AT 250 WORDS)
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Class II antigen-associated invariant chain mRNA in mouse small intestine.
MHC class II antigen-associated invariant (Ii) chain mRNA appears in mouse small intestine during postnatal development. Ii chain cDNA hybridizes to RNA from epithelial sheets dissociated from the lamina propria with EDTA. Of several mouse organs tested, only bone marrow and spleen contain higher levels of Ii chain mRNA than small bowel. Ii chain mRNA is not detected in stomach, colon, duodenum, testis, liver, submandibular gland, or L-cell RNA; brain contains a cross-reactive but uncharacterized sequence. cDNA amplification using primers specific for both Ii31 and Ii41 chain mRNAs showed that both forms occur in small intestine. These results support the conclusion that regulation of the class II Ii chain gene is associated with the ontogeny of intestinal immunity.
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Outcomes of direct coronary angioplasty for acute myocardial infarction in candidates and non-candidates for thrombolytic therapy.
Coronary angioplasty without prior thrombolytic therapy was performed in 383 patients with acute myocardial infarction (AMI). Patients were divided into 2 groups depending on whether they were candidates or non-candidates for thrombolytic therapy. Patients were not considered thrombolytic candidates if they: (1) presented in cardiogenic shock, (2) were greater than or equal to 75 years of age, (3) had had coronary artery bypass surgery or, (4) had a reperfusion time of greater than 6 hours. Thrombolytic and nonthrombolytic candidates had similar rates of reperfusion (92 vs 88%), nonfatal reinfarction (6.0 vs 5.9%) and recurrent myocardial ischemia (1.8 vs 0%). Thrombolytic candidates had a lower mortality rate (3.9 vs 24%, p less than 0.0001) and a lower incidence of bleeding (4.6 vs 10.9%, p less than 0.05). Improvement in left ventricular ejection fraction at follow-up angiography was 4.4% in thrombolytic and 10.5% in nonthrombolytic candidates (p less than 0.002). Ejection fraction improved most in patients with anterior wall AMI (7.7% in thrombolytic candidates, 15.1% in nonthrombolytic candidates) and in patients with reperfusion times greater than 6 hours (14.2%). These outcomes suggest that direct coronary angioplasty is a viable alternative method of reperfusion in patients with AMI who are candidates for thrombolytic therapy. Nonthrombolytic candidates are a high-risk group of patients. Direct coronary angioplasty may be beneficial in certain subgroups, especially for patients in cardiogenic shock and for patients presenting greater than 6 hours after the onset of chest pain with evidence of ongoing ischemia.
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L-tryptophan associated eosinophilia-myalgia syndrome.
Environmental chemicals are increasingly incriminated in the pathogenesis of several disease states. The eosinophilia-myalgia syndrome is a recently described entity attributed to the ingestion of the normal dietary amino acid L-tryptophan. We describe a patient who fulfills criteria for the eosinophilia-myalgia syndrome and who was ingesting supplemental L-tryptophan. Exhaustive investigations failed to reveal other causes for her eosinophilia or her myalgic/neuropathic complaints, and she improved dramatically when she discontinued the L-tryptophan supplements. The mechanisms whereby this chemical may induce this syndrome are discussed.
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The in vivo depletion of V beta 17a+ T cells results in the inhibition of reticulum cell sarcoma growth in SJL/J mice. Evidence for the use of anticlonotypic antibody therapy in the control of malignancy.
Previous findings revealed that reticulum cell sarcoma (RCS) of SJL/J mice growth and survival depended on its ability to stimulate a potent host T cell response, by the means of a tumor-associated class II MHC molecule with IE-like specificities. Previously we presented evidence that the V beta 17a TCR+ clonotype of T cell was the predominant T cell involved in the host response to the tumor. We undertook our study to examine whether the depletion of the V beta 17a+ T cells, by the use of the anticlonotypic antibody, KJ23a, resulted in the inhibition of RCS tumor growth in vivo. We present evidence herein that supports this hypothesis. KJ23a-treated mice exhibited a complete reduction in T cells bearing the V beta 17a TCR. These mice exhibited a dramatic reduction in the in vitro proliferative response to RCS. Furthermore, the pretreatment of SJL/J mice with KJ23a mAb resulted in the complete loss in their ability to harbor RCS tumor. When tumor-bearing mice were treated with a single inoculum of KJ23a mAb within the first 7 days after the passage of tumor, the mice showed long term survival with diminishing tumor burden. These results demonstrated that the V beta 17a clonotype of T cells is required for the growth and maintenance of RCS tumor. Within the first 6 wk after tumor inoculation KJ23a-treated mice were capable of transferring tumor to naive syngeneic recipient mice despite the obvious lack of tumor growth in the treated donor animal. These results suggested that RCS tumors in the absence of V beta 17a+ T cells can persist for up to 6 wk in a state of "tumor dormancy." The predominant usage of the V beta 17a gene in RCS-specific T cells suggests that these T cells play an important role in the pathogenesis of RCS tumor. Furthermore, the positive therapeutic course taken by tumor-bearing mice upon the treatment with KJ23a mAb, demonstrates the enormous potential in anticlonotypic antibody therapy in the treatment of T cell-dependent tumors and diseases.
Animals↗
A spontaneous sarcoma dependent on host tumor-specific immune lymphocytes.
The immune surveillance theory postulates that spontaneous tumors are normally rejected by the immune system and appear only when they override host-immune recognition and rejection mechanisms. The present mini-review describes a spontaneous tumor system, the reticulum cell sarcomas (RCS) in SJL/J mice, that is dependent on host tumor-specific immune lymphocytes for growth. This continuous tumor-specific response results in tumor progression and death of the host. This tumor system contradicts the basic concept of immune surveillance. We propose as an explanation that some highly antigenic tumors, like the RCS, may have evolved in a non-autonomous fashion but, nevertheless, have lost regulatory controls of cell proliferation. In the RCS system, the tumor expresses Class II MHC I-E like specificities that are not expressed on the host cells and which selectively stimulate a subpopulation of I-E specific T cells, the V beta 17 a+ clonotype, leading to their expansion and continuous nurturing of the tumor via secreted lymphokines. This neoantigenic stimulation bypasses the tumor regulatory response that might have resulted if the tumor had not expressed neoantigens. Furthermore, passive administration of anti-clonotypic antibody to tumor-bearing mice results in tumor regression and long-term survival through removal of the tumor reactive T cells. Thus, in this tumor system, immunosuppressive treatments are the prescription for tumor rejection.
Animals↗
The SJL/J T cell response to both spontaneous and transplantable syngeneic reticulum cell sarcoma is mediated predominantly by the V beta 17a+ T cell clonotype.
Previous studies have revealed that the reticulum cell sarcoma (RCS) of SJL/J (H-2s, IE-) mice express an "IE-like" stimulatory tumor-associated antigen, the expression of which is requisite for stimulating host T cells necessary for tumor growth. Herein, we present evidence that the predominant T cells raised in the syngeneic response to both spontaneous and transplantable RCS tumors are of the V beta 17a TCR clonotype. The V beta 17a+ clonotype of T cells has been shown to interact with IE allogeneic specificities. We demonstrate that all four characterized RCS-specific T cell hybridomas stained positively for the anti-V beta 17a mAb, KJ23a. Additionally, KJ23a, when added to cocultures of the T cell hybridomas and RCS tumors, inhibited the release of IL-2 by the hybridomas. Further, KJ23a was shown to markedly inhibit the proliferation of SJL/J T cells when cocultured with either spontaneous or transplantable RCS tumor cells. When analyzed by flow cytometry, the T cell blast population raised in response to both spontaneous and transplantable RCS were greater than 80% KJ23a+. These T cells were brightly stained by the anti-CD4 mAb, Gk1.5, and, therefore, represent class II-responsive T cells. In corroboration of the in vitro data, T cells derived from mesenteric lymph nodes of RCS tumor-bearing mice had likewise undergone a similar expansion of V beta 17a+, CD4+ T cells. Together, these results indicate that KJ23a+ T cells play an important and predominant role in the response of SJL/J mice to spontaneous RCS tumors and provide further suggestive evidence that the stimulatory antigen(s) on the RCS tumor is IE or an "IE-like" molecule. Significantly, the important role V beta 17a+ T cells play in the response to RCS suggests a potential therapeutic role for KJ23a mAb in the intervention and prevention of RCS tumors in SJL/J mice.
Animals↗
Antibody-dependent cellular cytotoxicity (ADCC)-mediated destruction of human immunodeficiency virus (HIV)-coated CD4+ T lymphocytes by acquired immunodeficiency syndrome (AIDS) effector cells.
The acquired immunodeficiency syndrome (AIDS) is defined in clinical terms by the development of Kaposi's sarcoma and/or severe opportunistic infections in persons without predisposing conditions. A hallmark of the syndrome has been a decrease in the number of CD4+ T helper cells. The reduction in the frequency of the CD4+ lymphocytes has been postulated to be primarily the result of human immunodeficiency virus (HIV) tropism and cytophathogenicity for the T-cell subset. Yet only a small percentage of cells in actually infected with HIV. Recently, we provided evidence indicating that AIDS patients' natural killer cells can mediate normal levels of antibody-dependent cellular cytotoxicity (ADCC) despite exhibiting a defect in natural killer (NK) effector function (J Immunol 139:55, 1987). This finding prompted us to investigate whether AIDS patients' effector cells could mediate ADCC against circulating CD4+ T cells infected with or expressing HIV antigen. The findings reported herein demonstrate that AIDS effector cells can mediate lysis of CEM (CD4+ T-cell line) coated with HIV protein in the presence of HIV-specific antibody. Lysis was specific, as non-HIV-coated CEM or the addition of HIV-negative serum resulted in no lysis. We then examined HIV-coated peripheral blood-derived CD4+ T lymphocytes as targets in ADCC. We demonstrate that in the presence of HIV-specific antibody, HIV-coated CD4+ T lymphocytes serve as targets for ADCC by AIDS effector cells. The lytic activity obtained with AIDS effector cells was comparable to that obtained with normal effector cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Acquired Immunodeficiency Syndrome↗
Mechanism of defective NK cell activity in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. II. Normal antibody-dependent cellular cytotoxicity (ADCC) mediated by effector cells defective in natural killer (NK) cytotoxicity.
Our studies and other investigations have shown that NK effector cells can also mediate antibody-dependent cellular cytotoxicity (ADCC) through the use of the Fc gamma receptor on the NK cell membrane. Peripheral blood lymphocytes (PBL) derived from patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex exhibit a poor NK activity due to a defective "trigger" required for activation in the lethal hit stage of the NK lytic pathway. Consequently, it was important to delineate whether the defect in AIDS NK cells affected the ADCC function. By using the 51Cr-release assay, the ADCC cytotoxic activity of AIDS PBL was found to be within the normal range, despite the absence of significant NK activity. Several experiments corroborated that the same effector cells mediate both NK CMC and ADCC. Depletion of Fc gamma R-bearing cells resulted in elimination of both the ADCC and NK cytotoxic functions. Single cell analyses, using one- and two-target cell conjugates, revealed that the frequency of ADCC effector:target conjugates and the frequency of killer cells from AIDS PBL were comparable to the frequencies seen in the normal controls. However, when mixtures of NK and ADCC targets were used to form mixed two-target conjugates, the AIDS effector cells lysed only the bound ADCC target, whereas the normal effector cells lysed both the bound NK and ADCC targets. These results demonstrate clearly that the same NK/K effector cells from AIDS PBL, defective in NK activity, are not impaired in mediating ADCC activity. These findings were supported by the demonstration that AIDS PBL stimulated with ADCC targets, but not with NK targets, released NK cytotoxic factors, postulated mediators of the NK CMC reaction. These findings indicate that the NK/K cells in AIDS are triggered normally for ADCC activity but are not triggered for NK activity. Furthermore, the results indicate that the lytic machinery is not impaired in the AIDS NK/K cells.
AIDS-Related Complex↗
Receptors for C3b on the neutrophil surface associate with the cytoskeleton-containing cell residue subsequent to cell lysis with non-ionic detergent. Cytoskeletal-CR1 interactions.
Radioiodinated Fab' and F(ab')2 fragments were prepared from 57F monoclonal antibody which is specific for the C3b receptor (CR1) on human cells. We find that both Fab' and F(ab')2 fragments bind to CR1 on human neutrophils and then dissociate, at 0 degree C, with half-lives of 172 and 35 min, respectively. In addition to binding to cell surface CR1, both antibody fragments bind specifically to the isolated non-ionic detergent-insoluble cellular residue (NDIR) which remains after cell lysis and solubilization in Triton X-100. We also find that Fab' and F(ab')2 antibody fragments remain associated with the NDIR after the radiolabeled antibody fragments are allowed to bind to cell surface CR1, the unbound fragments removed, and the cells subsequently lysed in non-ionic detergent. Because the cytoskeletal matrix (together with the cell nucleus) makes up a substantial portion of the NDIR, these results suggest that some fraction of cell surface CR1 may be associated in vivo with the cytoskeletal matrix. However, post-lysis association of cell surface-CR1-antibody fragment complexes to the NDIR occurs. Examination of the binding kinetics of this interaction reveals that less than 10% of cell surface CR1 exists bound to the NDIR prior to cell lysis. While the nature of post-cell lysis association of CR1 with the NDIR is unknown, several modulating effects are noted. For example, binding of bivalent cross-linking agents to CR1 on cells followed by a 37 degrees C incubation is known to induce internalization of cell surface CR1. We find that binding of F(ab')2 antibody fragments under these conditions causes a 50% decrease in association of this 57F fragment to the NDIR. Pretreatment of the cells at 37 degrees C with the chemotactic peptide N-formyl-methionyl-leucylphenylalanine similarly caused a 50% decrease of (Fab'-labeled) CR1 association with the NDIR cell fraction. These results support the hypothesis that chemotactic peptide serves to enhance CR1-mediated adherence to C3b-bearing targets by increasing the density of CR1 on the cell surface rather than by inducing cytoskeletal-dependent, detergent-stable, CR1 redistribution on the cell surface.
Antibodies, Monoclonal↗
Emergency coronary angioplasty for acute myocardial infarction. Results from a community hospital.
Emergency coronary angioplasty was performed in 127 patients presenting to a community hospital with acute myocardial infarction. Reperfusion and successful dilatation were performed in 117 patients (92%) at 3.3 +/- 1.8 hours from the onset of pain. Eleven patients (8.6%) died, ten patients (7.9%) developed reocclusion, and ten patients (7.9%) required coronary bypass surgery during the initial hospitalization. Late restenosis occurred in 36% (27/76) of patients restudied or 27% (27/100) of patients at risk for restenosis. Ejection fraction improved in patients with patent vs occluded vessels (8.4% +/- 8.2% vs -4.1% +/- 6.0%) and improved most in anterior vs inferior vs posterolateral infarcts (11.0% +/- 8.4% vs 6.8% +/- 6.4% vs 2.6% +/- 7.5%). Posthospitalization follow-up in all patients (mean, 13.4 months) revealed only one late death. Of the patients followed up, 83% had no angina, and 17% of patients had mild angina. Our experience demonstrates that coronary angioplasty for acute myocardial infarction can be performed in the community hospital by an experienced cardiovascular laboratory team with a high success rate, a low reocclusion rate, an improvement in ejection fraction, and an excellent long-term prognosis. The community hospital setting allows early access to patients and creates the potential for early reperfusion and myocardial salvage.
Acute Disease↗
Anesthetic considerations for geriatric patients.
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