Biomedical subjects
Publications and source records attributed to E Sorkin.
Catastrophic antiphospholipid syndrome (CAPS) is an acutely devastating situation characterized by widespread thrombotic microangiopathy in the presence of elevated titers of antiphospholipid antibodies. We describe a 57-year old woman who underwent liver transplantation for primary sclerosing cholangitis and developed this malignant variant of the antiphospholipid syndrome.
Renal failure is a common finding in patients undergoing orthotopic liver transplantation. The aim of the present study was to evaluate the incidence, prognostic value of pre, intra and postoperative factors and severity of renal dysfunction in patients who undergo liver transplantation. Therefore, the records of 38 consecutive adult patients were reviewed. Renal failure was defined arbitrarily as an increase in creatinine (> 1.5 mg/dl) and/or blood urea (> 80 mg/dl). Three patients were excluded of the final analysis (1 acute liver failure and 2 with a survival lower than 72 hs.) Twenty one of the 35 patients has renal failure after orthotopic liver transplantation. Six of these episodes developed early, having occurred within the first 6 days. Late renal impairment occurred in 15 patients within the hospitalization (40 +/- 10 days) (Mean +/- SD). In he overall series, liver function, evaluated by Child-Pugh classification, a higher blood-related requirements and cyclosporine levels were observed more in those who experienced renal failure than those who did not (p < 0.05). Early renal failure was related with preoperative (liver function) and intraoperative (blood requirements) factors and several causes (nephrotoxic drugs and graft failure) other than cyclosporine were present in patients who developed late renal impairment. No mortality. No mortality was associated with renal failure. We conclude that renal failure a) is a common finding after liver transplantation, b) the pathogenesis of this complication is multifactorial and, c) in not related with a poor outcome.
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Tumor rechallenge following primary tumor excision elicits systemic anti-inflammation that occurs rapidly, affects granulocytes as well as macrophages and is more severe, longer in duration, and induced by fewer tumor cells than the macrophage specific anti-inflammatory effect sometimes seen after primary tumor challenge. Factors important in the pathogenesis of this abnormality are the following. First, primary tumor excision was required as defects did not occur when a second tumor was transplanted during primary tumor growth. Second, the abnormality was restricted to neoplastic cells since normal cells were unable to substitute for either primary or secondary tumor challenge. Third, the anti-inflammatory effect was not due to surgical trauma or local irritation. Fourth, defective inflammation occurred in syngeneic but not allogeneic rats, suggesting an immunological basis for the anti-inflammation. Fifth, elevated glucocorticoids, such as might be expected from an immunological reaction or release of IL-1, may be a contributing but not sole cause for the phenomenon.
We investigated whether the development of sympathetic innervation of the spleen is affected by lymphoid cells. Splenic noradrenaline (NA) levels of athymic nude mice (nu/nu) and normal thymus-bearing littermates (nu/+) were determined at different times during ontogeny. While no differences were detected at birth, higher splenic NA levels were found in 7-, 11-, and 21-day-old athymic mice. Thymus transplantation or thymocyte injection to newborn nude mice resulted in splenic NA levels comparable to those of normal nu/+ mice. Histochemical studies fully confirmed such differences. Taken together with previous studies, these results suggest that T lymphocytes or their products exert an inhibitory influence on sympathetic nerve fibers, thus leading to decreased NA content in the spleen. The data also illustrate the capacity of a nonneuronal cell in a peripheral organ to affect the process of autonomic innervation of this organ.
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The production and action of immunoregulatory cytokines, including interleukin-1 (IL-1), are inhibited by glucocorticoid hormones in vivo and in vitro. Conversely, glucocorticoid blood levels were increased by factors released by human leukocytes exposed to Newcastle disease virus preparations. This activity was neutralized by an antibody to IL-1. Therefore the capacity of IL-1 to stimulate the pituitary-adrenal axis was tested. Administration of subpyrogenic doses of homogeneous human monocyte-derived IL-1 or the pI 7 form of human recombinant IL-1 to mice and rats increased blood levels of adrenocorticotropic hormone (ACTH) and glucocorticoids. Another monokine, tumor necrosis factor, and the lymphokines IL-2 and gamma-interferon had no such effects when administered in doses equivalent to or higher than those of IL-1. The stimulatory effect of IL-1 on the pituitary-adrenal axis seemed not to be mediated by the secondary release of products from mature T lymphocytes since IL-1 was endocrinologically active when injected into athymic nude mice. These results strongly support the existence of an immunoregulatory feedback circuit in which IL-1 acts as an afferent and glucocorticoid as an efferent hormonal signal.
Transplantation of 2 chemically (DMBA, MCA)-induced tumors into syngeneic female or male DA strain rats elicited hormonal changes during tumor growth. Plasma levels of 7 different hormones were studied. Tumor cells in syngeneic recipients produced a biphasic decrease in insulin, an early increase in prolactin, and a late-phase decrease in thyroxine. Corticosterone decreased in female tumor bearers but increased in males. This difference may reflect differences in the tumors transplanted. Male rats had a decrease in testosterone during the late phase of tumor growth, while females had a biphasic decrease in progesterone and a late-phase increase in growth hormone. The tumors used were moderately immunogenic in syngeneic recipients. However, tumor transplantation to allogeneic recipients produced an early decrease in growth hormone and no change in insulin, corticosterone or thyroxine. Further, transplantation of normal liver cells to syngeneic or allogeneic recipients produced no hormonal abnormalities. This study demonstrates that hormonal changes which are not observed with normal cells or allogeneic tumor transplantation can occur within 2 days of syngeneic tumor transplantation. Progressive tumor growth is characterized by a worsening endocrine imbalance which involves multiple hormone systems.
Inflammation in progress at one site decreases edema formation at a second and separate inflammatory focus. This clinically important phenomenon is known as counter-irritation. Since its effect on leukocyte responses has not been defined, we investigated in rats the systemic anti-inflammatory effect of local irritant injection on cellular emigration, particularly monocytes. Macrophage accumulation at a subcutaneous inflammatory site was severely depressed by prior intraperitoneal irritant injection despite continued macrophage accumulation in the peritoneal cavity and normal circulating monocyte levels. The phenomenon also existed in the peritoneal cavity to subcutaneously administered irritants and involved PMNs as readily as macrophages. Anti-inflammation occurred only when the counter-irritant was injected before or simultaneously with the measured inflammatory response while the degree and duration of inhibition depended upon the nature and amount of counter-irritant injected. These studies demonstrate that local inflammation inhibits leukocyte reactivity. Transplantation of syngeneic tumor but not normal cells also produced a depression in macrophage inflammatory responses. This inhibition differed from counter-irritation by not affecting granulocytes and by being transient despite tumor persistence.
Anergy associated with cancer or major surgery may derive from the systemic antileukocyte effect induced by local inflammatory reactions (counter-irritation). Since the mechanism of the latter phenomenon is unknown, we approached the problem by asking if tolerance develops to repeated local irritant injections. Our results demonstrate that both tolerance and cross-desensitization occur rapidly to inflammatory agents (inflammagens) such as proteose peptone, thioglycollate, and carrageenan but not to the mitogens Con A, PHA-P, or LPS which also induce local inflammation. We interpret this data as supporting the notion that a common mechanism underlies the counter-irritant action of inflammagens but that injection of mitogens induces an additional mechanism of anti-inflammation distinguished from the former by its lack of tolerance induction. Based upon cross-desensitization experiments, we show that the anti-inflammatory effect of surgical amputation is analogous to that induced by inflammagens. In contrast, the systemic anti-inflammatory effect of tumor bearing, like that induced by mitogens, resists cross-desensitization suggesting that its mediation is not caused solely by the mechanism common to the counter-irritant action of inflammagens or major surgery.
Macrophage tumoricidal activity requires a constant influx of macrophages but many transplanted cancers inhibit macrophage inflammatory responses. In this paper we address the issue of whether or not autochthonous tumors induced by either mammary tumor virus (MTV) in C3H/He mice or ultraviolet (u.v.) radiation in C3H/He or BALB/c mice also depress macrophage responses. Anti-inflammatory activity was not observed either prior to or during growth of these autochthonous tumors. Rather, the opposite was observed: strongly immunogenic u.v.-induced tumors which were rejected upon transplantation to syngeneic hosts had enhanced macrophage responses and more intratumoral macrophages than those mice whose tumors were transplantable. Transplantation of MTV-induced tumors selected for more aggressive tumors which had fewer intratumoral macrophages. In both MTV- and u.v.-induced tumors inflammatory responses of mice bearing serially transplanted tumors often differed from mice with autochthonous tumors. Our results demonstrate that anti-inflammation is probably not required for emergence and growth of these autochthonous tumors, that strongly immunogenic tumors may actually enhance macrophage responses and that the effect of tumor bearing on macrophage inflammation is a characteristic of the tumor, including its site and host of origin, its immunogenicity and its transplant generation.
Products are released in vitro by mitogen stimulation of human peripheral blood mononuclear cells or rat spleen cells which increase corticosterone blood levels when injected into normal rats. We report that an almost pure population of human peripheral blood lymphocytes in mixed lymphocyte culture stimulated with phytohaemagglutinin also produces a glucocorticoid increasing factor(s). The product equivalent to the amount released by 5 X 10(5) cells increased corticosterone levels four-fold and also increased ACTH levels. When rats were hypophysectomized or treated with dexamethasone to block ACTH output, no corticosterone increase was noted following administration of glucocorticoid increasing factor(s) (GIF). Similar results were obtained with supernatants of rat spleen cells stimulated with concanavalin A. We conclude that GIF has no direct action on the adrenals in vivo and that a functional pituitary gland is essential for its action. The presented data taken together with those described earlier suggest the existence of a glucocorticoid associated immunoregulatory feedback circuit.
Concepts and facts concerning immune-neuroendocrine interactions are discussed. The immune response elicits endocrine, autonomic, and brain functional changes. These changes can be mediated by soluble factors released by activated immunologic cells. As a result of these immune-neuroendocrine interactions the content of powerful agents such as hormones, neurotransmitters, and neuropeptides in the microenvironment of immunologic cells is modified. This leads to external immunoregulatory signals imposed upon autoregulatory mechanisms.
Autochthonous and transplanted tumors induced by 3-methylcholanthrene-impregnated paraffin pellets in DA rats and C57BL/6 mice were analyzed for effects on macrophage inflammatory responses. Tumors emerged in 40% of carcinogen-treated rats with a mean latency of 8.1 months. During the latent period, rats treated with carcinogen versus rats treated only with paraffin had a higher frequency of depressed macrophage responses, which, however, did not alter either tumor latency or incidence. Tumors emerged in 70% of carcinogen-treated mice with a mean latency of 110 days. Prior to tumor emergence, mice treated with carcinogen or paraffin had a higher frequency of depressed responses than untreated control mice, and such abnormalities in the presence of carcinogen were positively associated with tumor development. Macrophage responses were not altered in rats or mice bearing large autochthonous tumors, although emerging tumors in rats but not in mice were associated with a modest inhibition in macrophage responses. Autochthonous tumors that did not induce macrophage abnormalities did so in syngeneic recipients upon tumor transplantation.
Leukocyte accumulation at inflammatory sites probably involves chemotactic migration of the cells, and it is often presumed that abnormalities in cell accumulation derive from defective chemotaxis. The latter contention was examined by measuring the chemotactic response of leukocytes obtained from the circulation during conditions associated with depressed cellular inflammatory reactions. In two transplanted-tumor models induced by different chemical carcinogens in DA strain rats, monocyte chemotaxis was normal or enhanced while macrophage accumulation at inflammatory foci was severely curtailed. Late pregnancy in outbred Wistar rats depressed macrophage accumulation to peritoneal irritants while enhancing monocyte chemotaxis. Irritant-induced anti-inflammation (counterirritation) in Wistar rats decreased both polymorphonuclear leukocyte and macrophage accumulation during inflammation but enhanced the chemotactic activity of the corresponding cells obtained from the circulation. We concluded that in vitro chemotactic measurements were not predictive of cellular accumulation during inflammation in these conditions and that an intrinsic defect in chemotaxis was insufficient to explain anti-inflammation associated with cancer, pregnancy, or counterirritation.
An inverse relation between endogenous levels of glucocorticoids and splenic mass and cellularity was detected. Decreased endogenous corticosterone blood levels result in an increased number of immunoglobulin-secreting cells in the spleen, a fact that cannot be attributed only to the expansion of the lymphoid cell mass. The opposite phenomenon was observed in animals with high corticosterone blood levels, which showed reduced numbers of immunoglobulin-secreting cells. It is concluded that endogenous glucocorticoid levels contribute to the control of B cell activity and possibly to the interaction of these cells with other immunologic cells.
A decreased noradrenaline turnover in the hypothalami of rats was observed at the peak of the immune response to sheep red blood cells. The decrease in noradrenergic neuronal activity was mimicked by injection of soluble r mediators released by immunological cells activated in vitro. Noradrenaline also tended to decrease in the brainstem but not in the residual brain. It is suggested that products released from activated immunological cells during the immune response may induce the previously described autonomic and endocrine mechanisms that contribute to immunoregulation.
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