Melanoma-associated immunosuppression through B cell activation of suppressor T cells.
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Retraction Notice↗
Biomedical subjects
J L Ninnemann
Publications and source records attributed to J L Ninnemann.
Retraction of papers published in The Journal of Trauma.
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Retraction Notice↗
Immunology of intermingled skin grafts in rats: preliminary results.
Successful treatment of severely burned patients with the Chinese method of intermingled skin grafting has raised questions concerning the pathophysiological and immunological mechanisms which allow the survival of mixed allogeneic and autologous tissue. In creating a rat model and measuring systemic immunological status by means of mixed lymphocyte reactions (MLR) and histology, we found comparable levels of sensitization in intermingled and allografted rats; however, allografts were rejected and intermingled graft survival was significantly prolonged. We interpret our results to indicate that the survival of intermingled grafts is dependent upon an as yet undefined local protective effect exerted by the presence of auto-skin islands in the allotypic portion of intermingled grafts.
Animals↗
Trauma peptide induction of lymphocyte changes predictive of sepsis.
Post-trauma immunosuppression is characterized by T-cell subpopulation changes and the presence of a low molecular weight suppressive active peptide (SAP), which suppresses T-cell blastogenesis and neutrophil chemotaxis. This study evaluated post-trauma T-cell antigens and suppressive active peptide/T-cell interactions to determine if the suppressive active peptide concentrations predictive of sepsis can cause changes in antigen expression predictive of sepsis. Human lymphocyte markers and differentiation antigens were analyzed post-trauma using flow cytometry for markers predictive of sepsis. Changes induced by purified suppressive active peptide incubated with normal human lymphocytes were similarly analyzed by flow cytometry. SAP concentrations for incubation were chosen which correlated with concentrations in patients developing clinical sepsis. Significant T-cell changes in patients who developed sepsis include: decreased total T-cells, decreased helper cells, decreased natural killer cells, increased Ia expressing mononuclear cells, increased activated T-cells, (L22) and increased IL-2 expressing cells (TAC). Suppressive active peptide can activate T-cells and cause significant increased expression of IL-2 receptors and natural killer cells. Other T-cell changes following trauma predictive of sepsis seem to occur independent of in vitro incubation with suppressive active peptides. IL-2 expressing cells are known to be more readily suppressed by the suppressive peptide. Suppressive peptide activation and subsequent inhibition of T-cells suggests a potential way to explain suppressive peptide-induced immunosuppression following trauma.
Adult↗
Trauma peptide-mediated prostaglandin E2 biosynthesis: a potential mechanism for trauma-induced immunosuppression.
In vitro exposure of peripheral-blood-adherent mononuclear cells or amnion cells to nanomolar quantities of a trauma-associated immunosuppressive peptide resulted in an increased biosynthesis of prostaglandin E2 (PGE2). Trauma peptide enhanced prostaglandin E2 biosynthesis by as much as 425% compared to buffer controls. The addition of trauma peptide to mixed lymphocyte cultures significantly inhibited [3H]thymidine incorporation by human peripheral blood lymphocytes. Addition of indomethacin (an inhibitor of prostaglandin biosynthesis) to mixed lymphocyte cultures did not significantly abrogate the immunosuppressive activity of the peptide. These results indicate that suppression of T lymphocyte blastogenesis by trauma peptide is probably mediated by at least two mechanisms: (1) by increased PGE2 biosynthesis, induced by trauma peptide, and (2) through a non-cyclooxygenase-mediated pathway.
Dinoprostone↗
Immunosuppressive effects of a trauma-induced suppressor active peptide.
The isolation and partial characterization of an immunosuppressive glycopeptide from sera of severely burned patients has previously been reported. Recently, a monoclonal antibody to this factor and an enzyme linked immunosorbent assay for detection of the peptide have been developed. The presence of the peptide in elevated quantity has been demonstrated in serum of patients with multiple blunt trauma as well as thermally injured patients. It was determined that the peptide is capable of suppressing neutrophil chemotaxis and T-cell blastogenesis as measured by MLR. Inhibition of B-cell blastogenesis induced by the peptide as measured by LPS mitogen-induced proliferation was demonstrated to be less sensitive to suppression. Further, it appears that activated T lymphocytes, those expressing increased IL-2 receptors, are more sensitive to suppression by the peptide at lower concentrations than are nonactivated T lymphocytes.
Bacterial Infections↗
The immunosuppressive activity of C1q degradation peptides.
We have previously reported the existence and activity of a collagen-like, low molecular weight, suppressive peptide complex in patients with greater than 40% BSA burns. Since C1q participates in the inflammatory response and contains a collagen-like sequence, we have tested, in vitro, the putative generation and immunologic activity of C1q peptide fragments under physical conditions present in burned patients. Nanogram quantities of heat- and enzyme-generated fragments of C1q were shown to be suppressive in vitro to neutrophil chemotaxis, and the mixed lymphocyte response (MLR). The addition of lymphocytes pretreated with C1q fragments suppressed ongoing MLR, indicating the activation of suppressor cells by the peptides. Rabbit anti-C1q globulin was found to reduce the suppressive activity of the collagen-like suppressor which was isolated from human burn sera. Our results therefore suggest that C1q may be an early source of degradation peptides which have strong nonspecific immunosuppressive activity following thermal injuries.
Burns↗
Reversal of SAP-induced immunosuppression and SAP detection by a monoclonal antibody.
A murine monoclonal IgG antibody (MAb) to column-isolated trauma-induced suppressor active peptide (SAP) was produced and utilized in these studies for the further characterization of SAP. Specificity of the antibody was confirmed by enzyme-linked immunosorbent assay (ELISA), passive immunoblotting, and reversal of SAP-induced neutrophil chemotaxis inhibition. ELISA analysis revealed binding of anti-SAP MAb to a serum protein present in both whole burn and normal serum, but only to burn serum using a less than 25,000-mw serum fraction. This suggests that SAP may be an injury-induced degradation product of a greater than 25,000-mw serum protein. Immunoblotting using a less than 25,000-mw burn serum fraction demonstrated MAb binding to a single low molecular weight protein band. Using the MAb in an ELISA immunodiagnostic procedure, it appeared that SAP levels were significantly elevated in the sera of burned patients who died from their injuries compared to levels in sera of controls or patients who survived.
Animals↗
Long-term depressed immune function in patients splenectomized for trauma.
Peripheral blood from asplenic trauma patients (ASP) was analyzed for immunoglobulin concentrations, complement levels, T- and B-lymphocyte populations, and mitogen response of T cells, and compared to a similar analysis performed on the blood of normal controls (C). The interval from splenectomy to testing averaged 1,471 +/- 193 days (mean +/- SEM) in the ASP. Total lymphocyte count averaged 2,941 +/- 234 in the ASP with a T-cell count of 2,030 +/- 182 and a B cell count of 351 +/- 58. The average control lymphocyte count of 1,769 +/- 147 was significantly less than ASP (p less than 0.001) as were the T-cell count of 1,328 +/- 107 (p less than 0.005) and the B-cell count of 124 +/- 18 (p less than 0.001). Responses to PHA were diminished in ASP lymphocytes by 38% at 3 days (p less than 0.01) and by 49% at 5 days (p less than 0.001) when compared to C. Levels of IgM were significantly decreased (p = 0.05) in ASP. Levels of C3, C4, and C5 were similar in ASP and C. These data demonstrate persistent abnormalities in immune function in adult ASP without underlying lymphoreticular disorders and suggest a possible explanation for the increased septic risk in this patient group.
Adolescent↗
Clinical and immune status of burn patients.
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Bacterial Infections↗
Immunologic parameters in burned patients: effect of therapeutic interventions.
Complex immunologic alterations occur following thermal injury. To further delineate the intricacies of the immune response, a longitudinal profile of immunologic parameters was investigated in burned patients with specific reference to clinical criteria (resuscitation, plasma exchange, surgical excisions, sepsis). During a 17-month period, 26 adult patients with a mean age of 32.6 years and a mean burn size of 45.6% TBSA were evaluated with serial (twice weekly) assays of immunocompetence. The immunologic variables monitored included complement components, fibronectin, immunoglobulins, acute-phase reactants, serum proteins, catecholamines, and the mixed lymphocyte reaction. Resuscitation from burn shock and clinical sepsis were associated with a wide array of serologic abnormalities and lymphocyte suppression. Plasma exchange and surgical excision and grafting procedures were also characterized by multiple serologic changes and improvement in lymphocyte function. No specific serologic parameter correlated well with cellular function; however, patterns of humoral alterations were consistently present and may represent a combined effect.
Adult↗
Suppression of in vitro lymphocyte and neutrophil responses by a low molecular weight suppressor active peptide from burn-patient sera.
Thermal injury produces profound pathophysiological changes in the severely burned patient. Primary among these is the modulation of immunity, leading to episodes of immunosuppression and thus increasing the risk of sepsis and possible death. We herein report the isolation of a low molecular weight suppressor active peptide (SAP) which appears to be responsible for many of the observed immunologic changes in burned patients. SAP suppressed T-lymphocyte blastogenesis in the mixed lymphocyte reaction (MLR) and inhibited neutrophil chemotaxis (CTX) in vitro. Characterization of SAP revealed a complex structure comprised of (1) a peptide component rich in glycine, serine, and alanine; (2) a carbohydrate component containing sialic acid; and (3) a fatty acid component, tentatively identified as prostaglandin E. The immunosuppressive activity of SAP is dependent upon the presence of all three structural components. The molecular weight of SAP was estimated to be 3654 as determined by Amicon cell ultrafiltration and amino acid analysis. The isoelectric point of SAP was estimated by chromatofocusing and ion-exchange chromatography to be between 3.2 and 3.6. We hypothesize that the suppressor active peptide may be comprised of cellular or tissue components released into the circulation at the time of injury.
Amino Acids↗
Hemolysis and suppression of neutrophil chemotaxis by a low molecular weight component of human burn patient sera.
During the past year, we have reported the isolation and characterization of a low molecular mass (less than 5000 Da) complex (SAP), having profound immunosuppressive activity, found in the plasma of patients with major thermal injuries. Our continued studies have revealed that non-cytotoxic inhibition of neutrophil chemotaxis by SAP is paralleled by erythrocyte hemolysis by the same compound. Both neutrophil inhibitory and hemolytic activities appear to be a function of the peptide portion of SAP (determined by sensitivity to trypsin and pronase), which is augmented by the presence of sialic acid in the complex (activity eliminated by the addition of neuraminidase). The lipid portion of SAP, which is critical to its neutrophil immunosuppressive activity, does not appear to participate in erythrocyte hemolysis. Hemolytic activity of SAP is not due to protease activity, and does not appear to be receptor dependent. However, it is completely dependent upon the presence of calcium. The hemolytic activity of SAP appears to be abrogated by the addition of cerium nitrate, leading to a hypothesized relationship of SAP to the immunological activity of "burn toxin", previously described in detail (Schoenenberger, G.A. (1975) Monogr. Allergy 9, 72-139).
Burns↗
Circulating toxins in human disease: a viable concept?
Many clinical and biological effects have been attributed to the presence of mediators in the general circulation of patients after injury, a major operation, or the onset of certain diseases. Often, the term toxin is applied in an attempt to describe these circulating mediators. In the discussion that follows, cutaneous burn toxin is cited as an example and an opinion is ventured concerning the continued acceptance of both the term toxin and the toxic concept in modern medicine.
Animals↗
The effect of surgical excision and grafting procedures on postburn lymphocyte suppression.
Previous reports have stressed the immunosuppressive effects of major surgical procedures. In this study, 30 adult patients with a mean burn size of 42.8% TBSA and a mean age of 31.9 years underwent 78 surgical excision and grafting (E/G) procedures. The mean surface area excised was 2,373 cm2, with a mean blood transfusion requirement per E/G of 3,355 cc or 1.4 cc/cm2. The suppressive effect of burn serum was assayed in mixed lymphocyte cultures. Before E/G, burn serum caused a mean 42.2 +/- 3.3% suppression of normal lymphocyte blastogenesis; serum suppressive activity following E/G was reduced to 29.1 +/- 2.9% (p less than 0.005). The mean duration of improvement in lymphocyte function was 5.0 days. E/G procedures which achieved complete burn wound closure were more effective in restoring lymphocyte immunocompetence. E/G has a significant beneficial effect on restoring lymphocyte responsiveness in burn patients. Preliminary evidence suggests that this effect is related to blood transfusions.
Adolescent↗
Definition of a burn injury-induced immunosuppressive serum component.
We and others have previously observed that immunologic activity can often be restored to both lymphocytes and neutrophils by removing them from the burn environment, leading to the conclusion that burn serum contains substances capable of suppressing immunologic function. The present studies were initiated to better define the serum component(s) responsible for this immunosuppression. The majority of immunosuppressive activity vs. both neutrophil chemotaxis and mixed lymphocyte cultures contained in large-volume serum samples obtained from three patients with greater than 40% body surface area flame burns was found to reside in a less than 25,000 mw fraction of serum obtained by Amicon ultrafiltration. A single suppressive serum component was isolated by precipitation and resuspension, followed by ion-exchange chromatography using an SP Sephadex C-25 column. Purity of the samples was verified by SDS slab-gel electrophoresis, and immunosuppressive activity was confirmed vs. both lymphocytes and neutrophils. Analysis of this isolated burn-associated suppressor indicates: a) a molecular weight of between 1,000 and 5,000 daltons; b) a complex composition containing a protein component, a lipid component, and a carbohydrate component; c) a structure which is heat stable, pH stable and unaffected by treatment with trypsin, proteinase K, DNAse, and RNAse; and d) a noncytotoxic immunosuppressive mode of action. It appears that the suppressive activity is dependent upon a prostaglandin portion of this low molecular weight complex.
Adult↗
The effect of plasma exchange on lymphocyte suppression after burn.
Circulating mediators have been implicated in the pathophysiology of immunodepression after burn injury, suggesting the beneficial effect of plasma exchange in immunorestoration. In this study, 19 adult patients with a mean burn size of 52.2% of total body surface area and mean age of 33.4 years underwent 51 plasma exchange procedures in five different clinical settings, without complication. The suppressive effect of burn serum was assayed in mixed lymphocyte cultures. The mean (+/- SEM) suppression by burn serum drawn prior to plasma exchange was 61.9% +/- 3.6%, while that following plasma exchange was 27.3% +/- 2.7%. The lymphocyte response decrease 55.1% +/- 4.4% in suppressive activity. The mean duration of improvement in lymphocyte function was 4.8 days. Plasma exchange has a significant beneficial effect in restoring lymphocyte immunocompetence in burned patients in a number of clinical settings.
Adolescent↗
Participation of prostaglandin E in immunosuppression following thermal injury.
The participation of prostaglandin E in the regulation of the immune response via suppressor cell activation, and the release of large quantities of these prostaglandins as a result of thermal injuries, are both (separately) well documented. In this report, we present evidence that prostaglandin E plays an important immunologic role following thermal injuries. The concentration of PGE in sera from patients with major burn injuries is generally high (1,000-3,000 pg/ml), and these same sera are often significantly suppressive to in vitro lymphocyte responsiveness. We have documented the ability of PGE (both that which is commercially synthesized, and that isolated in fractions obtained from burned patient sera by column chromatography) to suppress mixed lymphocyte cultures, and show that such suppression can be blocked by either delipidation of serum fractions, or by the addition of monospecific anti-PGE to the cultures. We also report evidence suggesting the existence of a serum protein with a molecular weight of approximately 5,000 daltons which appears to be necessary for the expression of the immunosuppressive properties of PGE contained in patient sera.
Adolescent↗