Further characterization of the role of the lipoxygenase pathway in the in vivo allograft response.
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Biomedical subjects
Publications and source records attributed to M L Jordan.
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The NK cells and the alloimmune CTL recovered from a rejecting sponge graft both possess the surface determinant AGM1. Both systemic and local treatment of sponge-bearing mice with anti-AGM1, results in severe inhibition of NK activity and alloimmune CTL activity recovered from the graft. From this evidence it is tempting to speculate that cells exhibiting the characteristics of NK cells may differentiate into alloimmune CTL.
The release of potent immunoregulatory substances in the mixed inflammation of a rejecting allograft could significantly modify the accumulation and subsequent function of the infiltrating lymphocyte population. Prostaglandin E2 (PGE2) is a major cyclooxygenase metabolite of arachidonic acid that is released at sites of inflammation in vivo at concentrations reported to inhibit the functional responses of bulk lymphocyte populations. In order to more directly assess the role of PGE2 as a modulator of the immune response, we examined its effects on in vitro lymphocyte random migration (using a modified Boyden chamber assay), proliferation to a variety of stimuli, and both allospecific and lectin-mediated cytotoxicity using several C57BL/6 anti DBA/2 T cell clones characterized functionally as helper (n = 5), cytotoxic (CTL, n = 4), or cytotoxic only in the presence of lectin (L-CTL, n = 1). Helper cell migration and proliferation to secondary MLC supernatant or recombinant IL-2 were inhibited (P less than 0.001) by physiologic concentrations (10-100 ng/ml) of PGE2. In contrast, the migration, proliferation and cytotoxicity of all lytic clones (CTL or L-CTL) were not affected by these or higher concentrations (1000 ng/ml) of PGE2. Indomethacin (10(-6) M) did not modify lymphocyte responses to PGE2. The effects of PGE2 on helper cell function were completely reversible by cell washing. These data show that the effector functions of cloned T cells are inhibited by PGE2 in a subset-specific fashion fashion and suggest that components of immunologically initiated inflammation may play a heretofore unrecognized role in locally modulating the behavior of distinct T cell subsets at the rejecting allograft.
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The inflammatory response may play a critical role in determining the ultimate fate of the allograft. Certain inflammatory mediators derived from the arachidonic acid lipoxygenase pathway (e.g., leukotriene B4), stimulate T cell function in vitro, but their role in allograft rejection is unknown. Nordihydroguaiaretic acid (NDGA) inhibits both the lipoxygenase (LO) pathway and T cell function in vitro. In this study, we investigated the effects of systemic LO inhibition with NDGA on the in vivo generation of allospecific and natural killer (NK) effector cells and arachidonic acid metabolites from sponge matrix allografts in mice. In control animals, generation of both allospecific cytolytic and NK cells increased progressively up to 12 days after grafting. Sponge cell synthesis of both leukotriene B4 (LTB4) and the cyclooxygenase product prostaglandin E2 (PGE2) could also be detected over this period. Recipient NDGA treatment (50 mg/kg/day) impaired both the accumulation and the specific cytotoxic potential of lymphocytes in allograft. Compared with control animals (1196 +/- 30 pg/10(6) cells), cells from recipients of NDGA produced significantly less LTB4 (55 +/- 10 pg/10(6) cells, p less than 0.01) but produced normal amounts of PGE2 (340 +/- /255 +/- 22 pg/10(6) cells, p = NS), thus proving the specificity of the NDGA treatment on LO pathway function. We conclude that cells capable of metabolizing arachidonic acid by both pathways accumulate in sponge allografts, but LO activity is specifically suppressed by systemic NDGA. Furthermore, systemic LO inhibition reduces the nonspecific inflammatory component, as well as allospecific cytolytic and NK generation, without compromising animal survival. These studies suggest that suppression of specific components of the inflammatory response associated with allograft rejection by LO inhibition may be a useful approach to selective immunosuppression.
NK cells, present in sponge allografts between all genetic barriers tested, are present at the graft site several days before alloimmune CTL are detected. Both NK and alloimmune CTL possess the AGM1 surface marker. Systemic as well as local treatment with AGM1 antisera depletes NK activity as well as alloimmune CTL at the graft site. NK cells may function at the graft site to facilitate development of alloimmune CTL and/or NK cells may themselves differentiate into alloimmune CTL.
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The effects of the arachidonic acid metabolites prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) on the in vitro random migration of cloned murine T lymphocytes (derived from limiting dilution analysis of a C57BL/6 anti-DBA/2 mixed leukocyte culture) were examined. Experiments were also performed to study the effects of the cyclooxygenase inhibitor indomethacin on both random lymphocyte migration and lymphocyte migration in the presence of PGE2. The responses of cloned lymphocytes to PGE2 and LTB4 were compared with those of unsensitized lymph node lymphocytes. PGE2 at 100 ng/ml significantly inhibited (p less than 0.001) the in vitro migration of helper clones of T lymphocytes, but had no effect on random migration of cytotoxic T cells or helper independent cytotoxic (HIT) cloned cells. In contrast, LTB4 significantly (p less than 0.001) enhanced the random locomotion of helper, cytotoxic, and "HIT" cloned cells at 0.1 and 0.3 ng/ml. The effects of both PGE2 and LTB4 were found to be completely reversible by cell washing. Indomethacin (10(-7) M) did not alter random migration of any of the clones, and in particular, did not affect the inhibition of helper lymphocyte migration induced by PGE2. Unsensitized bulk lymph node lymphocyte migration was not affected by either PGE2 or LTB4. The results suggest that modulation of lymphocyte locomotor function by environmental stimuli may depend on cellular activation, and the locomotor responses of activated lymphocytes to arachidonic acid metabolites may be subset specific.
From 1976 to 1983, 13 living related and 54 cadaver renal transplants were done in 62 patients more than 50 years old. Patients with no coronary or myocardial disease upon coronary angiography were selected preferentially for transplantation. Over-all 1-year patient and graft survival rates were 88 and 70 per cent, respectively. Among cadaver recipients graft survival was improved (p less than 0.001) when prophylactic antilymphoblast globulin was used. There were fewer steroid-related complications (p less than 0.001) in recipients managed with a low dose rather than a high dose maintenance prednisone regimen. With careful patient selection and a steroid-sparing immunosuppressive regimen, renal transplantation can be done safely in older recipients with no increased risk of death or graft loss.
It is a well-understood principle of public health--and of disease control in general--that preventive efforts must be consistent with the natural history of a targeted disease. Governmental standards-setting and enforcement policies in occupational health confuse short-term strategies for safety hazard control with long-term disease control. Recent decisions in mining to rely on "significant and substantial" acute risk are incompatible with medical and epidemiological evidence on the nature and progress of chronic disease in many industries.
From 1977 to 1984, renal autotransplantation was attempted in 16 pediatric and young adult patients with renal artery disease, ranging in age from 10 months to 21 years. Renal revascularization was indicated as treatment for severe hypertension in 15 patients and to prevent rupture of an arterial aneurysm in one patient. The reasons for undertaking renal autotransplantation were branch renal artery disease requiring extracorporeal revascularization (n = 14), abdominal aortic hypoplasia (n = 1), and renal artery disease in a small infant (n = 1). Renal revascularization was successfully accomplished in 14 of 16 patients, including one patient who underwent staged bilateral extracorporeal repairs. Obliteration of the inferior vena cava and iliac veins precluded autotransplantation in one patient and a nephrectomy was done. In one patient extracorporeal ligation of an inaccessible renal arterial branch was accomplished with autotransplantation. Currently all 16 patients are normotensive with excellent renal function. Extracorporeal surgery and autotransplantation have been important additions to the surgical armamentarium for renal artery disease.
Nineteen patients were examined to determine the clinical potential of magnetic resonance imaging (MRI) for evaluation of renal transplants. A 0.6-T cryogenic magnet and spin-echo technique with varying pulsing factors were used. T1-weighted images were best for differentiating the cortical and medullary parts of the transplanted kidney. Of the six living-related transplants with good renal function that were imaged, five demonstrated good corticomedullary differentiation (CMD) and one faint CMD. Three transplants with acute rejection were imaged, and all demonstrated a decrease in CMD and decrease in overall signal intensity compared with baseline. No CMD was seen in the three chronically rejecting transplants imaged. The appearance of cadaveric transplants and acute tubular necrosis was quite variable. All perinephric fluid collections were well depicted by MRI. Lymphoceles could be distinguished from hematomas. MRI may prove to be a useful adjunct in the evaluation of renal transplants and perinephric fluid collections.
From 1970 to 1980, 341 consecutive renal transplants were performed in 307 patients at our hospital. Operative technique was uniform and performed by a single surgeon. Acute arterial thrombosis occurred in 12 kidneys (3.5 per cent) and venous thrombosis occurred in 3 (0.9 per cent). All of these kidneys were lost. Renal artery stenosis, diagnosed in 17 kidneys (4.9 per cent), resulted from surgical technique or rejection and was associated with hypertension in all cases. Of these kidneys 5 responded to drug therapy alone, 4 to transluminal angioplasty and 5 to surgical reconstruction. Three grafts were lost. Vascular complications occurred in 9 per cent of our patients. The results suggest that factors other than surgical technique alone can contribute to the incidence of vascular complications.
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