RESUMEN
OBJECTIVE: To assess at serial intervals the production of interleukin-12 (IL-12) by monocytes/macrophages from the peripheral blood of injured patients and control subjects, and using a mouse model to confirm human findings and explore the effectiveness of low-dose IL-12 therapy in restoring resistance to infection after injury. SUMMARY BACKGROUND DATA: Serious injury is associated with loss of function of the T helper 1 lymphocyte phenotype, but little is known about IL-12 production in injured patients. The authors previously reported that early, moderate-dose IL-12 therapy in a mouse model of burn injury restored resistance to a later infectious challenge (cecal ligation and puncture, CLP). However, the efficacy of clinically relevant low-dose IL-12 therapy carried out to or beyond the time of septic challenge remains to be tested. METHODS: Peripheral blood mononuclear cells (PBMCs) and adherent cells were obtained from 27 patients with major burns or traumatic injury and 18 healthy persons and were studied at serial intervals for IL-12 production stimulated by bacterial lipopolysacharide (LPS). PBMCs from 18 of the same patients were studied for IL-10 production as well. IL-12 production by adherent cells from the spleens of burn or sham burn mice was studied at serial intervals after injury to confirm the human findings. Low-dose IL-12 or vehicle was given every other day to groups of burn and sham burn mice, which were then challenged with CLP on day 10, and survival was determined. Finally, spleens were harvested from burn or sham burn animals receiving low-dose IL-12 or vehicle after CLP. After splenic cellularity was determined by hemocytometer, splenocytes were cultured and production of tumor necrosis factor-alpha, interferon-gamma, and IL-10 were assessed by immunoassay. RESULTS: Adherent cells from patients' PBMCs produced significantly less IL-12 than normal PBMCs after injury, reaching a nadir 8 to 14 days after injury. Stimulation of whole PBMCs by LPS indicated that at 8 to 14 days after injury, IL-12 production by PBMCs was significantly lower and IL-10 production was significantly higher than that of PBMCs from healthy persons. Low-dose IL-12 therapy significantly increased survival after CLP. Splenocytes from burn mice treated with IL-12 had significantly increased production of TNF-alpha and IF-beta, both before and after CLP, when compared with vehicle-treated burn animals. IL-10 production by bum splenocytes remained high after IL-12 treatment. Splenic cellularity increased after IL-12 treatment in burn mice. CONCLUSION: The capacity to produce IL-12 by adherent cells of the monocyte/macrophage lineage is significantly reduced after serious injury in humans and in a mouse burn model. In humans, there is a reciprocal relation between diminished IL-12 production and increased IL-10 production at approximately 1 week after injury. Low-dose IL-12 therapy in the mouse burn model markedly increased survival after a septic challenge, even when treatment was carried beyond the onset of sepsis. Low-dose IL-12 treatment in the mouse increased production of proinflammatory mediators important in host defense and at the same time maintained or increased production of IL-10, an important antiinflammatory cytokine.
Asunto(s)
Infecciones Bacterianas/inmunología , Quemaduras/fisiopatología , Interleucina-12/biosíntesis , Interleucina-12/uso terapéutico , Infección de Heridas/inmunología , Heridas y Lesiones/fisiopatología , Adulto , Animales , Femenino , Humanos , Interleucina-10/biosíntesis , Macrófagos/inmunología , Masculino , Ratones , Persona de Mediana Edad , Monocitos/inmunología , Bazo/citologíaRESUMEN
BACKGROUND & AIMS: The role of the cytokine interleukin 2 (IL-2) has long been recognized as central to normal immunologic function and defense against infection after burns and trauma, but little effort has been directed towards its role in acute pancreatitis (AP), which also has a high mortality related to sepsis. This study investigated the potential role of IL-2 in mice with diet-induced AP. METHODS: AP was induced in mice by 10 days of feeding a choline-deficient, ethionine-supplemented diet. T-helper (CD4) cells were estimated, and T-cell mitogen-stimulated splenocyte proliferation and IL-2 production in vitro were measured on days 3, 7, and 10. RESULTS: Significant reduction in IL-2 production was found on day 3 (32%; P < 0.05) and day 10 (48%; P < 0.005). Administration of intraperitoneal lipopolysaccharide on day 10 was associated with reduced IL-2 production (P < 0.025) 4 hours later and 90% mortality in animals with AP. In vivo therapy with recombinant IL-2 improved in vitro IL-2 secretion (P < 0.05) and reduced lipopolysaccharide-induced mortality (P = 0.036). CONCLUSIONS: Murine diet-induced AP is associated with impaired immune function and increased susceptibility to sepsis and may be a valuable tool in the investigation of immunomodulation in AP.
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Interleucina-2/biosíntesis , Pancreatitis/inmunología , Enfermedad Aguda , Adyuvantes Inmunológicos , Animales , Recuento de Linfocito CD4 , Endotoxinas/efectos adversos , Femenino , Interleucina-2/uso terapéutico , Lipopolisacáridos/efectos adversos , Activación de Linfocitos , Ratones , Ratones Endogámicos , Pancreatitis/metabolismo , Pancreatitis/terapia , Proteínas Recombinantes/uso terapéutico , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Major thermal or traumatic injury often results in abnormalities of immune function, and these abnormalities contribute to the increased susceptibility to infection observed in these patients. Abnormalities of T-cell function, including decreased proliferation and secretion of cytokines are observed following major injury and, conversely, there is markedly increased monokine production. Thus, therapy of this syndrome might logically be aimed at modulating the immune system to upregulate T-cell function and downregulate monocyte hyperactivation. Pentoxifylline (PTX), a methylxanthine derivative, has been shown to be therapeutically effective in several animal models. The purpose of this study was to evaluate PTX and its effect on cytokine production in a mouse model of thermal injury and to study its effect on survival after septic challenge. The results show that PTX therapy after injury can restore T-cell production of IL-2 and downregulate the hyperactive macrophage secretion of proinflammatory cytokines. However, improvement in survival resulting from this therapy following thermal injury and septic challenge depends on timing of dosage.
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Quemaduras/inmunología , Infecciones/inmunología , Pentoxifilina/farmacología , Animales , Quemaduras/complicaciones , Quemaduras/terapia , Células Cultivadas , Citocinas/biosíntesis , Dinoprostona/biosíntesis , Infecciones/complicaciones , Interleucina-2/biosíntesis , Interleucina-6/biosíntesis , Lipopolisacáridos/farmacología , Masculino , Ratones , Pentoxifilina/uso terapéutico , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
BACKGROUND: Among the fundamental immunologic abnormalities induced by serious traumatic or thermal injury are alterations in T cell activation, reduced lymphocyte interleukin-2 (IL-2) production, and associated depression of T lymphocyte proliferation. This study attempts to localize the cellular mechanisms underlying abnormal IL-2 production in thermal injury. METHODS: Following National Institutes of Health guidelines, 150 A/J mice were anesthetized, subjected to a 20% full-thickness scald burn injury or sham burn, and killed at intervals from 4 to 21 days later; splenocytes were harvested for in vitro studies. For measurement of IL-2 production, cells were cultured with either concanavalin A or a combination of the phorbol ester PMA, which directly activates protein kinase C, and the calcium ionophore A23187, which increases intracellular calcium. Cytokine mRNA expression was measured by Northern blot analysis and IL-2 production by bioassay. RESULTS: Both IL-2 production and IL-2 mRNA expression were consistently suppressed in concanavalin A-stimulated cells from burned mice compared with sham burns. This suppression of IL-2 and IL-2 mRNA also occurred when T cells were activated with PMA and A23187, bypassing the earlier stages of the signal transduction mechanism. IL-1 beta and tumor necrosis factor-alpha mRNA expression were consistently increased in burned animals, indicating that decreased IL-2 mRNA expression was specific to IL-2 and not representative of a global decrease in cytokine mRNA expression. CONCLUSIONS: These results suggest that the principal cellular abnormalities that result in altered T cell activation and IL-2 production after thermal injury lie downstream of the initiating signal transduction events and before IL-2 gene transcription.
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Quemaduras/metabolismo , Interleucina-2/biosíntesis , Animales , Calcimicina/farmacología , Interleucina-1/genética , Interleucina-2/genética , Activación de Linfocitos , Masculino , Ratones , ARN Mensajero/análisis , Linfocitos T/inmunología , Acetato de Tetradecanoilforbol/farmacología , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
It has previously been shown by this laboratory that immunomodulation of thermally injured animals with low-dose interleukin-1 (IL-2) and indomethacin (Indo) improves survival following septic challenge. Lymphokine-activated killer (LAK) cells have been shown to be effective in certain viral infections and to act in synergy with IL-2 in the treatment of certain types of cancer. We have studied the effect of LAK cells in combination with IL-2 and Indo in a murine model of thermal injury and sepsis. Male A/J mice received a 25% scald burn injury or sham burn and were randomized into five groups: (a) sham/vehicle, (b) burn/vehicle, (c) burn/IL-2 (250 U) + Indo (5 micrograms), (d) burn/LAK cells (2 x 10(6) cells), or (e) burn/LAK cells+IL-2+Indo and were treated accordingly for 6 days following injury. LAK cells were generated by in vitro IL-2 treatment of syngeneic spleen cells for 72 hr and cytotoxic activity was confirmed by standard 51Cr release assay using natural killer (NK)-sensitive and NK-resistant targets. In the groups receiving LAK cells they were administered on Day 1 and Day 6 postinjury. On Day 10, septic challenge by cecal ligation and puncture (CLP) or splenectomy, for in vitro studies, was performed. Five-day survival after CLP was 80% in the sham/vehicle group compared to 0% in the burn/vehicle group (P < 0.01). IL-2/Indo and LAK/IL-2/Indo improved survival to 25% (P < 0.05) and 57.1% (P < 0.01), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Quemaduras/mortalidad , Interleucina-2/uso terapéutico , Células Asesinas Activadas por Linfocinas/inmunología , Sepsis/mortalidad , Animales , Quemaduras/inmunología , Citocinas/biosíntesis , Activación de Linfocitos , Masculino , Ratones , Sepsis/inmunología , Tasa de SupervivenciaRESUMEN
Critical illness is associated with both immunosuppression and glutathione deficiency. We determined if in vivo depletion of glutathione would adversely affect immune status. Rats with normal glutathione levels and those with glutathione stores depleted by diethyl maleate underwent analysis of splenocyte function and mesenteric lymph node lymphocyte function. Lymphocytes of the spleen and mesenteric lymph nodes were tested for concanavalin A proliferative response and interleukin 2 production. Tumor necrosis factor and interleukin 6 secretion by splenic adherent cells was also measured. Glutathione-depleted animals had significantly decreased lymphocyte proliferation and decreased production of tumor necrosis factor and interleukin 6 but unaltered interleukin 2 production. These findings indicate that in vivo glutathione deficiency impairs macrophage and T-cell function. Because glutathione depletion may occur in sepsis, trauma, and shock, treatments that help maintain glutathione levels may enhance immunocompetence and thus improve the ability of patients to recover from critical illness.
Asunto(s)
Enfermedad Crítica , Glutatión/deficiencia , Tolerancia Inmunológica/inmunología , Inmunidad Celular/inmunología , Macrófagos/inmunología , Linfocitos T/inmunología , Animales , Concanavalina A , Modelos Animales de Enfermedad , Estudios de Evaluación como Asunto , Glutatión/química , Glutatión/inmunología , Interleucina-2/biosíntesis , Interleucina-2/química , Interleucina-2/inmunología , Interleucina-6/biosíntesis , Interleucina-6/química , Interleucina-6/inmunología , Ganglios Linfáticos/citología , Activación de Linfocitos/inmunología , Ratas , Ratas Wistar , Bazo/citología , Linfocitos T/química , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/química , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Studies of the immune response of patients following major injury have identified significant abnormalities, some of which may be due to the effects of endotoxin. To evaluate the effect of endotoxin on the immune system without conflicting variables, we studied 18 normal, healthy male volunteers each on two occasions. In one study, Escherichia coli endotoxin was administered intravenously at a dose of 4 ng/kg. In the other, saline was given. Blood for immune function studies was obtained at either 0, 4, or 24 hr (seven volunteers), 0, 1, and 4 hr (five volunteers), or 0, 4, and 6 hr (six volunteers) postinfusion. Peripheral blood mononuclear cells (PBMC) were isolated and adjusted to the same concentration. Measurements following endotoxin infusion were compared with those of the same volunteers following saline infusion and with those from normal ambulatory laboratory volunteers. Interleukin 1 (IL-1) production by adherent cells was significantly reduced at 1 hr post endotoxin infusion. Significant decreases in number of mononuclear cells, response to phytohemagglutinin (PHA), and production of IL-2 and IL-1 were observed by 4 hr after endotoxin infusion. No significant changes in percentages of monocytes, lymphocytes, or CD3, CD4, or CD8 lymphocytes were observed at any time. By 24 hr postinfusion all values had returned to normal or, in some cases, supranormal levels. Response to PHA by PBMC from volunteers 4 hr following endotoxin was completely restored by in vitro addition of recombinant human IL-2 but was only marginally improved by IL-1. In vitro addition of indomethacin to PBMC cultures responding to PHA reduced the suppression observed after in vivo endotoxin but also was not as effective as IL-2. In a fourth study, seven volunteers were treated as above either with two doses (800 mg each) of the cyclooxygenase inhibitor ibuprofen before endotoxin infusion or with ibuprofen alone. Ibuprofen pretreatment completely restored the PBMC response to PHA to normal and caused a significant decrease in the endotoxin-induced suppression of IL-2 production. However, the decrease in circulating PBMC number and adherent cell secretion of IL-1 was not affected by inhibition of the cyclooxygenase pathway. These results suggest that endotoxin has immunomodulatory effects on both adherent mononuclear-cell and T-lymphocyte function and that more than one mechanism is involved.
Asunto(s)
Endotoxinas/inmunología , Inmunidad Celular/inmunología , Adulto , Endotoxinas/administración & dosificación , Escherichia coli/inmunología , Humanos , Ibuprofeno/administración & dosificación , Infusiones Intravenosas , Interleucina-1/metabolismo , Interleucina-2/metabolismo , Activación de Linfocitos/inmunología , Masculino , Monocitos/inmunología , Fitohemaglutininas , Prostaglandina-Endoperóxido Sintasas/metabolismo , Linfocitos T/inmunologíaRESUMEN
Macrophage hyperactivity with increased production of tumor necrosis factor, interleukin 6, interleukin 1, and prostaglandins has been demonstrated in the injured patient, but the effect of this on the clinical outcome is unclear. We studied the effect of combination interleukin 1 beta and indomethacin sodium therapy on macrophage hyperactivity and survival after sepsis in a murine burn model. Macrophage interleukin 1, interleukin 6, and tumor necrosis factor alpha production were all significantly increased 10 days after thermal injury. Treatment with recombinant human interleukin 1 beta in combination with indomethacin significantly reduced this overproduction of cytokines to normal levels, and this was associated with an improvement in survival after septic challenge (52% survival in interleukin 1 beta-indomethacin-treated group compared with 22% in burned vehicle control mice). Burned mice that received either interleukin 1 beta or indomethacin alone demonstrated tumor necrosis factor and interleukin 6 production and survival intermediate between the interleukin 1 beta-indomethacin-treated group and the vehicle control group. Control of macrophage hyperactivity is associated with improved survival from subsequent sepsis and offers a potential new strategy for the treatment of immune dysfunction in thermally injured patients.
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Quemaduras/inmunología , Indometacina/farmacología , Interleucina-1/farmacología , Macrófagos/efectos de los fármacos , Sepsis/tratamiento farmacológico , Animales , Quemaduras/sangre , Quemaduras/tratamiento farmacológico , Quemaduras/mortalidad , Indometacina/uso terapéutico , Interleucina-1/metabolismo , Interleucina-1/uso terapéutico , Interleucina-6/sangre , Interleucina-6/metabolismo , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos A , Ratones Endogámicos , Sepsis/sangre , Sepsis/etiología , Bazo/citología , Tasa de Supervivencia , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Depression of cell-mediated immunity in patients following severe traumatic injury has been well documented in vitro and in vivo. However, the exact mechanism of this defect is still controversial. In this study, we have investigated the ability of injured patients' peripheral blood mononuclear cells (PBMC) to produce two important immunoregulatory molecules, interleukin 1 (IL 1) and interleukin 2 (IL 2). Eighteen traumatic injury patients were studied during the course of their hospital stay and their results compared with a group of 18 normal age- and sex-matched controls. The results showed the following. (1) Production of IL 2 by normal PBMC in response to optimal doses of mitogen may vary with sex as well as age. (2) Adherent mononuclear cells from trauma patients produced at least as much IL 1 as normals. (3) IL 2 production, however, was markedly suppressed (normals, 1.6 +/- 0.2 U; traumatic injury, 0.6 +/- 0.1 U; P = 0.001) and persisted for as long as 50 days postinjury. OKT4+ cells were not significantly decreased at any time, nor were OKT8+ suppressor/cytotoxic cells increased at any time. Decreased IL 2 production in patients treated with steroids or those who were septic was not different from that in those patients who were not treated with steroids or were not septic. These results suggest that the cause of the defect in IL 2 production in traumatic injury patients is not related to a lack of the IL 1 signal, producer T cells, or Ia+ monocytes or to increased suppressor T cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Síndromes de Inmunodeficiencia/etiología , Interleucina-1/biosíntesis , Interleucina-2/deficiencia , Monocitos/metabolismo , Heridas y Lesiones/complicaciones , Corticoesteroides/farmacología , Humanos , Inmunidad Celular , Síndromes de Inmunodeficiencia/inmunología , Interleucina-2/biosíntesis , Activación de Linfocitos , Monocitos/inmunología , Sepsis/complicaciones , Heridas y Lesiones/inmunologíaRESUMEN
We studied the production of the two major mediators of cellular immune responses, Interleukin 1 (IL-1) and Interleukin 2 (IL-2), by the peripheral blood mononuclear cells of 23 burn patients (16 men, seven women, mean age 48.9 years) compared with 23 matched controls (16 men, seven women, mean age 46.7 years). Serial measurements were made of IL-1 production by adherent mononuclear cells after stimulation with lipopolysaccharide and of IL-2 production by lymphocytes after stimulation with phytohemagglutinin (PHA). Eighty determinations of IL-2 production by lymphocytes from 12 patients with greater than 30% body surface area burn revealed a mean IL-2 production of 0.71 u as compared with a mean of 1.23 u for patients with less than 30% burns (p = 0.04). Patients with greater than 30% body surface area burns had significantly reduced IL-2 production (p less than or equal to 0.05) until 60 days after injury, whereas those with smaller burns had reduced IL-2 production only at 20-29 and 30-39 days postburn. Nine burn patients with systemic sepsis showed significantly lower IL-2 production (p = 0.03) at 10-29 days postburn than nonseptic patients, and significantly less IL-2 production during septic episodes. Eight patients with greater than 50% suppression of lymphocyte response to PHA produced less IL-2 (0.4 u) than patients with less than 50% suppression, (1.07 u, p = 0.004). IL-1 production was significantly elevated as compared with controls (4.45 u vs. 3.6 u, p = 0.05) early after injury, but was subsequently within the normal range regardless of burn size. The percentage of circulating helper T-lymphocytes, the principal source of IL-2, was also reduced, although this did not always correlate with IL-2 production, which remained depressed after recovery of the helper T-cell population. These results indicate that failure to produce IL-2, a powerful mediator of cellular immune responses, is an important mechanism underlying the defective cell mediated immunity seen in burn patients.
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Quemaduras/metabolismo , Interleucina-2/biosíntesis , Adulto , Anciano , Anticuerpos Monoclonales/inmunología , Infecciones Bacterianas/etiología , Quemaduras/complicaciones , Femenino , Humanos , Interleucina-1/biosíntesis , Interleucina-2/deficiencia , Activación de Linfocitos , Linfocitos/clasificación , Masculino , Persona de Mediana EdadRESUMEN
Thirty-four patients undergoing elective abdominal aortic aneurysmectomy were studied, and they were randomly allocated to a "fed group receiving amino acid dextrose solutions intravenously and fat emulsions or an "unfed" group receiving standard postoperative care. Cell-mediated immunity was measured by lymphocyte count, the in vitro response to the T-cell mitogen PHA and determination of T-cell subsets using monoclonal antibodies. Serum suppressive activity was measured by the ability of the sera of the patient to suppress the response of normal lymphocytes to PHA. Feeding was continued for three to five days postoperatively until satisfactory oral intake was achieved. There was no significant improvement in lymphocyte count or blastogenesis postoperatively in the "fed" group, and operation did not lead to any alteration in the ratio of T-cell subsets, although there was a fall in T-cell count (OKT3 positive cells). We conclude that short term parenteral nutrition in well nourished patients, postoperatively, does not abrogate the depression of cell-mediated immunity which occurs after extensive operative procedures.
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Tolerancia Inmunológica , Inmunidad Celular , Nutrición Parenteral , Cuidados Posoperatorios , Anciano , Anticuerpos Monoclonales/análisis , Aorta Abdominal , Aneurisma de la Aorta/cirugía , Ensayos Clínicos como Asunto , Femenino , Humanos , Técnicas In Vitro , Recuento de Leucocitos , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Necesidades Nutricionales , Distribución Aleatoria , Factores de TiempoRESUMEN
Skin testing with four recall antigens was performed serially in 21 patients after a major thermal burn. We looked for a correlation between the occurrence of anergy, the presence of immunosuppressive serum, and the impairment of the lymphocyte-proliferative response to phytohemagglutinin (PHA). Serum cortisol, endotoxin, and prostaglandin E2 (PGE2) levels were also measured in the serum or plasma. When anergy developed, it became apparent early in the course of the illness. It did not correlate closely with the severity of the burn, but was associated with mortality. There was a good correlation between anergy and coexisting serum suppression of lymphocyte activation in vitro. This serum immunosuppressive activity was not related to serum cortisol, PGE2, or plasma endotoxin levels. Anergy also correlated with coexistent impairment of patient peripheral blood lymphocyte activation by PHA. These results suggest that both immunosuppressive serum and an impaired lymphocyte response to mitogens are associated with anergy in burn patients and confirm that the development of anergy is an index of poor prognosis.
Asunto(s)
Quemaduras/inmunología , Hipersensibilidad Tardía/inmunología , Terapia de Inmunosupresión , Activación de Linfocitos/efectos de los fármacos , Adulto , Anciano , Quemaduras/mortalidad , Dinoprostona , Endotoxinas/sangre , Humanos , Hidrocortisona/sangre , Técnicas In Vitro , Persona de Mediana Edad , Mitógenos/farmacología , Fitohemaglutininas/farmacología , Pronóstico , Prostaglandinas E/sangre , Pruebas CutáneasRESUMEN
Recent experimental evidence has suggested that circulating suppressor leukocytes play an important role in mediating the suppression of immunity seen in burn patients. In order to shed further light on the relationship between suppressor cells and depressed cellular immunity 22 patients were studied (mean age 37) who had suffered severe burns of greater than 30% body surface area. Simultaneous studies were performed on 14 control laboratory personnel (mean age 32). Monoclonal antibodies were used to identify T-lymphocyte subsets known to have suppressor/cytotoxic (OKT8) and helper/inducer (OKT4) function, respectively. In addition, serial measurements were made of the response of circulating lymphocytes to the T-cell mitogen phytohemagglutinin (PHA). An inversion of the normal ratio between suppressor/cytotoxic and helper/inducer subsets (normal 0.55:1, postburn 1.4:1; p less than 0.001) occurred soon after burn injury, reached a peak in five to seven days and then returned gradually to normal levels by 14 days. A diminished response of patients' lymphocytes to PHA (57 +/- 10% SD suppression as compared with normal controls at five to seven days) corresponded with high suppressor to helper cell ratios and returned to normal at the same time. Functional assays, which recognize only high levels of activity, demonstrated circulating suppressor cells in nine patients during this same period but became negative by 14 days. These early immunologic modulations were not predictive of morbidity or mortality. Later in the postburn course, systemic sepsis in eight patients was associated with a return of increased suppressor to helper cell ratios and decreased mitogen (PHA) responsiveness. At this time functional assays demonstrated circulating suppressor cells in six patients. Five of these six patients died of sepsis. It was concluded that severe burn injury regularly induces an early transient increase in circulating suppressor cells accompanied by a depression of lymphocyte activation. A later (greater than 14 days postburn) increase in suppressor cells to levels detectable by functional assays is closely correlated with mortality from sepsis.
Asunto(s)
Quemaduras/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Anticuerpos Monoclonales , Quemaduras/sangre , Humanos , Recuento de Leucocitos , Activación de Linfocitos/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Linfocitos/clasificación , Persona de Mediana Edad , Fitohemaglutininas/farmacología , Linfocitos T/clasificaciónAsunto(s)
Formación de Anticuerpos , Líquido Ascítico/inmunología , Citotoxicidad Inmunológica , Adulto , Anciano , Animales , Células Productoras de Anticuerpos/inmunología , Cromatografía en Gel , Femenino , Técnica de Placa Hemolítica , Humanos , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Persona de Mediana Edad , Metástasis de la Neoplasia , Fitohemaglutininas/farmacología , OvinosRESUMEN
Both suppressor lymphocytes and serum immunosuppressive factors have been found in patients who have had major thermal burns, and may inhibit host resistance to the bacteria invariably present in burn wounds. However, the relationship and clinical importance of these two manifestations of impaired immune reactivity are poorly understood. Eighteen patients (aged 20-84 years) with full thickness burns of varying severity have been studied, and the clinical course related to the presence of nonspecific immunosuppressive serum and circulating suppressor lymphocytes. Serum factors capable of suppressing the phytohemagglutinin (PHA) response of normal lymphocytes usually appeared early and were detected in 15 of the 18 patients at some time during the illness. Thirteen of these patients developed systemic infection. Depression of the PHA response of peripheral blood lymphocytes was much less common and was associated with this finding died. No patients who did not have severe depression of the lymphocyte response to PHA died. Nonadherent leukocyte (NA leukocyte) populations exhibiting a depressed PHA response were capable of suppressing the PHA response of normal human lymphocytes and, therefore, contained suppressor cells.
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Suero Antilinfocítico/inmunología , Quemaduras/inmunología , Tolerancia Inmunológica , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Quemaduras/mortalidad , Células Cultivadas , Humanos , Técnicas In Vitro , Infecciones/epidemiología , Activación de Linfocitos/efectos de los fármacos , Persona de Mediana Edad , Fitohemaglutininas/farmacología , Pronóstico , Factores de TiempoRESUMEN
In order to clarify the relationship between anergy and immunosuppressive activity in the serum, we studied 46 previously well patients before and at three, five, seven and 28 days after surgery. Delayed hypersensitivity was measured by skin testing with four common recall antigens, and serum immunosuppressive activity was determined by the ability of the patient's serum in 10% concentration to suppress by 50% or more the phytohemagglutinin (PHA) stimulation of normal human lymphocytes as compared to pooled normal serum. Prior to surgery, all patients manifested delayed hypersensitivity to one or more antigens, and no patient had immunosuppressive serum. Fifteen patients underwent minor surgery under general anesthesia and did not develop anergy or immunosuppressive serum. Thirty-one patients underwent major cardiovascular surgery. Thirteen of these patients became anergic by day 3 after operation, and 11 of the 13 developed immunosuppressive serum. Eighteen patients maintained delayed hypersensitivity after major surgery, and only three developed immunosuppressive serum. The correlation between anergy and immunosuppressive serum was highly significant (p < 0.001). There was a significant difference in the degree of suppressive activity in the serum of the anergic and reactive patient groups for each postoperative day studied until day 28, when there was recovery of delayed hypersensitivity and lack of immunosuppressive serum. The occurrence of postoperative anergy and immunosuppressive serum was not related to the patient's age, sex, number of perioperative blood transfusions or duration of anesthesia but was associated with an increase in postoperative infectious complications (p < 0.05) and in postoperative days in the hospital (p < 0.01). Pooled immunosuppressive serum from anergic patients was fractionated by ion exchange chromatography, gel filtration and preparative high voltage electrophoresis. The majority of the immunosuppressive activity could be accounted for by an electrophoretically homogenous polypeptide-containing fraction not identified in the serum of patients undergoing minor surgery or in normal individuals. We conclude that anergy occurring after major operative trauma is associated with the appearance of a circulating immunosuppressive molecular species and that these events are in turn associated with increased patient morbidity and increased length of hospitalization.