Defective Neutrophil Research Articles

Advances in pathophysiology, diagnosis, and treatment of neutrophil defects

Recent literature relevant to neutrophil defects in pediatric patients spans a wide range of interests. Significant new observations on the molecular pathology, pathogenesis, prenatal diagnosis and therapy, as well as thorough clinical reviews of neutrophil defects appeared during the past year. Diverse types of congenital neutropenias are documented to respond to granulocyte-colony stimulating factor and granulocyte-macrophage colony-stimulating factor and differences in responses may yield insight into the pathogenesis of chronic benign neutropenia, Kostmann's agranulocytosis, and the neutropenia of glycogen storage disease 1b. Leukocyte adhesion deficiency can be diagnosed in utero; however, the assays are crude and do not yet take advantage of the rapidly increasing knowledge of transcriptional or translational abnormalities in CD11b expression. In chronic granulomatous disease (CGD), rapidly increasing knowledge of the molecular basis of gene defects in X-linked CGD led to identification of point mutations as well as gross deletions of the gp91phox gene that cause CGD. Furthermore, advances in the therapy of CGD with interferon-7 are now paired with suggestions that increase in nitroblue tetrazolium reduction by monocytes may underlie the efficacy of interferon-y in CGD. Recently improved methods of analyzing cytoskeletal dynamics in the neutrophil has led to the description of a novel neutrophil defect with defective motility and defective actin polymerization, and studies of acquired neutrophil defects point to the importance of transforming growth factor (3 and cytokines as modulators of defective neutrophil function in several immunoregulatory defects associated with increased susceptibility to bacterial infection.

Hematopoietic growth factors as adjuncts to antiretroviral therapy.

Anemia and neutropenia are common complications of HIV infection. Antiretroviral therapy with zidovudine exacerbates bone marrow suppression by inhibiting proliferation of blood cell progenitor cells. In addition, treatment for opportunistic infections or malignancies can involve the use of myelosuppressive drugs. As a consequence, severe anemia and neutropenia can result, thereby limiting the utilization of antiretroviral drugs. Since antiretroviral therapy can increase survival, drugs that ameliorate myelosuppression are important adjuncts in the treatment of HIV-infected patients. Three hematopoietic growth factors are effective in the treatment of anemia or neutropenia. In four placebo-controlled trials, erythropoietin (EPO) at doses up to 600 U/kg/wk decreased mean transfusion requirements by 37%, increased mean hematocrit by 4.5% and corrected anemia in the majority of patients receiving zidovudine over a 12-week period. In a separate study, granulocyte colony-stimulating factor (G-CSF) corrected leukopenia and isolated neutrophil defects in 22 patients with AIDS without altering HIV expression. When erythropoietin was added to the regimen, combined G-CSF and EPO corrected both anemia and leukopenia and lessened subsequent zidovudine toxicity. Similarly, granulocyte macrophage-colony-stimulating factor (GM-CSF) corrected leukopenia and pre-existing neutrophil defects in patients with HIV infection. In controlled and uncontrolled trials, GM-CSF also appears to reduce toxicity from zidovudine, ganciclovir, and antineoplastic therapy. New combinations of hematopoietic stimulants are being used to decrease the toxicity from combination antiretroviral therapy with alpha interferon and cytotoxic chemotherapy in the treatment of AIDS-related malignancies.(ABSTRACT TRUNCATED AT 250 WORDS)

Neutrophil chemotaxis, phagocytosis, and superoxide release in depressive illness

Recently, some authors have reported defective neutrophil phagocytosis during depression. The present study investigated neutrophil function in 19 healthy controls and in 41 depressed inpatients categorized according to DSM-III into minor, simple major, and melancholic depression. We determined neutrophil function by means of phagocytosis, chemotaxis, and superoxide release. The results show no significant differences in neutrophil function among any of the subtypes of depression and normal volunteers. This suggests that overall neutrophil function is normal during depression. Thus, neutrophils are unlikely to be involved in the increased susceptibility to physical illness of patients with depression.

Decreased neutrophil respiratory burst on exposure to cobalt-chrome alloy and polystyrene in vitro.

The effect of biomaterials on the superoxide-producing ability of neutrophils was studied. Human peripheral blood neutrophils were incubated with cobalt-base alloy (F-75) or polystyrene beads of a nonphagocytosable size. Respiratory burst activity was studied by measuring superoxide dismutase inhibitable reduction of cytochrome C. Neutrophils were found to release no more superoxide anion on incubation for up to 3 h with either material in a protein-free medium than controls without foreign material. However, the ability of neutrophils incubated with either biomaterial to subsequently respond to phorbol myristate acetate challenge was decreased (p less than 0.05). Chemical analysis of supernatants for the F-75 samples showed a high concentration of cobalt in the medium within 1 h of incubation. Minimal chromium and nickel was detected. No correlation could be demonstrated between metal in solution and the respiratory burst defect in neutrophils. Instead it appears that interaction of cells with either surface was the critical event in altering the response to phorbol myristate acetate. This observed functional defect may play an important role in rendering tissue around implanted biomaterials susceptible to infections.

Chronic adult periodontitis and burst progression may reflect local neutrophil defects due to perivascular hyaline deposits

Chronic adult periodontitis (CAP) is a common disease of the supporting tissues of teeth, and is a major cause of tooth loss. This disease is distinguished from more rare rapidly progressing forms of periodontitis, in which a variety of neutrophilic polymorphonuclear leukocyte (PMN) defects have been identified. PMN dysfunctions have, however, not been observed in CAP. In CAP, destructive episodes of the disease occur sporadically and independently in different parts of the mouth. In this paper, it is proposed that CAP is due to highly localized defects in PMN function. Impaired PMN function is suggested as resulting in the formation of a virulent bacterial plaque, which is capable of initiating periodontal pocket formation. A previously reported perivascular hyaline material may account for localized PMN defects, by reducing the number of PMNs entering affected sites. The proposed model may explain both the presence of CAP in otherwise normal patients, and the sporadic pattern of tissue destruction seen in this disease.

Neutrophil Function in Dogs with Congenital Ciliary Dyskinesia

In vitro neutrophil function was assessed in two English Springer Spaniel dogs, two Bichon Frise dogs, and one Chow Chow dog with congenital ciliary dyskinesia; three clinically normal English Springer Spaniel dogs that were presumed heterozygous for congenital ciliary dyskinesia; and five control dogs. Chemotaxis and random migration in affected and heterozygous dogs were found to be comparable to those of control dogs. Increased (P less than or equal to 0.05) neutrophil adhesion, antibody dependent cell-mediated cytotoxicity, iodination of proteins, and oxygen radical production in neutrophils from affected dogs were probably the result of chronic bacterial infection in vivo. Bacterial ingestion by neutrophils from the three heterozygous English Springer Spaniel dogs was significantly increased compared to control dogs but was not different from affected English Springer Spaniel dogs, suggesting a breed-related phenomenon. Significant decreases in neutrophil function were not seen in any of the dogs with congenital ciliary dyskinesia, indicating that a defective microtubular system is not shared by respiratory cilia and neutrophils and that defective neutrophil function does not contribute to respiratory infection.

An Inherited Defect of Neutrophil Motility and Microfilamentous Cytoskeleton Associated With Abnormalities in 47-Kd and 89-Kd Proteins

AbstractA 2-month-old male Tongan infant presented with fever, severe skin and mucosal infections, hepatosplenomegaly, thrombocytopenia, and normal neutrophil counts. While polymorphonuclear neutrophil (PMN) morphology was normal, several neutrophil motile functions were found to be altered in the patient. Furthermore, two siblings had died in infancy with a similar clinical picture, raising the possibility of an inherited neutrophil defect. Random migration and chemotaxis, assessed by the under agarose method, were profoundly impaired. Actin polymerization, as measured by flow cytometry of N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)phallaci- din (NBD-phallacidin)-stained PMNs, showed lower basal F-actin and a 1.75-fold increase in response to 10'7 mol/L formyl-methionyl-leucyl-phenylalanine (FMLP) compared with a 4.51-fold increase in control. Microscopic examination of NBD-phallacidin-stained PMN spread on glass showed decreased area of spreading and F-actin-rich filamentous projections distinct from control. The early phase of FMLP- induced right angle light scattering was absent, similar to the effect caused by cytochalasin-B (CB), an inhibitor of actin polymerization. Accordingly, FMLP induced secretion of elastase without the addition of CB. Staphylococcus aureus killing was 50% of control whereas superoxide production in response to FMLP and surface expression of CD11b were greater than twice normal. Partial defects in actin polymerization and scatter were seen in the parents and release of elastase, in the absence of CB, was also increased in both parents. Sodium dodecyl sulfate-polyacrylamide electrophoresis of whole cell proteins from the patient showed a marked decrease in an 89-Kd protein (8% of control) and a marked increase in a 47-Kd protein (4.2-fold). Both mother and father had decreased 89-Kd (77% and 42% of control) and increased 47-Kd proteins (2- and 3.4-fold), although neither had recurrent infections or chemotactic defects. These studies describe a new inherited actin dysfunction syndrome associated with severe propensity to fungal infection and draw attention to the proteins of apparent molecular weights of 89 Kd and 47 Kd, which may be of great importance in the regulation of actin polymerization in human PMNs.

An inherited defect of neutrophil motility and microfilamentous cytoskeleton associated with abnormalities in 47-Kd and 89-Kd proteins

A 2-month-old male Tongan infant presented with fever, severe skin and mucosal infections, hepatosplenomegaly, thrombocytopenia, and normal neutrophil counts. While polymorphonuclear neutrophil (PMN) morphology was normal, several neutrophil motile functions were found to be altered in the patient. Furthermore, two siblings had died in infancy with a similar clinical picture, raising the possibility of an inherited neutrophil defect. Random migration and chemotaxis, assessed by the under agarose method, were profoundly impaired. Actin polymerization, as measured by flow cytometry of N-(7-nitrobenz-2-oxa- 1,3-diazol-4-yl)phallacidin (NBD-phallacidin)-stained PMNs, showed lower basal F-actin and a 1.75-fold increase in response to 10(-7) mol/L formyl-methionyl-leucyl-phenylalanine (FMLP) compared with a 4.51- fold increase in control. Microscopic examination of NBD-phallacidin- stained PMN spread on glass showed decreased area of spreading and F- actin-rich filamentous projections distinct from control. The early phase of FMLP-induced right angle light scattering was absent, similar to the effect caused by cytochalasin-B (CB), an inhibitor of actin polymerization. Accordingly, FMLP induced secretion of elastase without the addition of CB. Staphylococcus aureus killing was 50% of control whereas superoxide production response to FMLP and surface expression of CD11b were greater than twice normal. Partial defects in actin polymerization and scatter were seen in the parents and release of elastase, in the absence of CB, was also increased in both parents. Sodium dodecyl sulfate-polyacrylamide electrophoresis of whole cell proteins from the patient showed a marked decrease in an 89-Kd protein (8% of control) and a marked increase in a 47-Kd protein (4.2-fold). Both mother and father had decreased 89-Kd (77% and 42% of control) and increased 47-Kd proteins (2- and 3.4-fold), although neither had recurrent infections or chemotactic defects. These studies describe a new inherited actin dysfunction syndrome associated with severe propensity to fungal infection and draw attention to the proteins of apparent molecular weights of 89 Kd and 47 Kd, which may be of great importance in the regulation of actin polymerization in human PMNs.

Role of Natural Killer Cells in Resistance to Systemic Cryptococcosis

These studies demonstrate that Cryptococcus neoformans infection induced a dose-dependent augmentation of splenic natural killer (NK) cell activity by bg/+, but not bg/bg mice. To directly assess the role of NK cells in resistance to C. neoformans, bg/+ and bg/bg mice were treated with anti-NK-1.1 monoclonal antibody (mAb). Anti-NK-1.1-treatment abrogated the augmented NK cell activity observed during C. neoformans infection in bg/+ mice. Anti-NK-1.1-treated bg/+ mice had higher C. neoformans colony forming units (CFU) in their lungs on days 3 and 7 after intravenous (i.v.) challenge than control bg/+ mice. Moreover, the number of C. neoformans CFU in the lungs of anti-NK-1.1-treated bg/+ mice on days 3 and 7 were similar to those observed for infected bg/bg mice. By day 14, however, no differences in C. neoformans CFU were evident in the lungs of anti-NK-1.1-treated and control bg/+ mice. Anti-NK-1.1-treatment did not alter either the growth of C. neoformans in the spleens, livers, kidneys, or brain of bg/+ mice or the susceptibility of bg/bg mice to systemic cryptococcosis. These studies suggest that NK cells do not play a role in resistance to systemic cryptococcosis in the spleen, but do appear to play an early, but transient role in resistance to C. neoformans in the lungs. Overall, congenital defects in polymorphonuclear neutrophils (PMNs) and macrophages (M phi s), in addition to defects in NK cells, contribute to the enhanced susceptibility of bg/bg mice to systemic cryptococcosis.

The Effect of Granulocyte Colony-Stimulating Factor (G-CSF) upon Burn-induced Defective Neutrophil Chemotaxis

Severe thermal injury results in impairment of granulocyte production and function. The ability to improve the functional capacity of neutrophils could contribute to a reduced morbidity and mortality from sepsis following thermal injury. Previous studies from this laboratory have shown that rhG-CSF increases the number of femoral marrow granulocyte progenitor cells and circulating neutrophils as well as the survival rate following burn wound infection. The studies reported here examine the effect of in-vivo administration of rhG-CSF on neutrophil chemotaxis following a burn injury and also following superimposed Pseudomonas burn wound sepsis in mice. Casein-elicited peritoneal neutrophils were harvested 72 hours after burn injury and 24 hours after infection. Chemotaxis was assessed using microchemotaxis chambers and 10(-5) M fMet-Phe as a chemoattractant. The number of neutrophils that migrated into the filter was used as an index of directed chemotaxis. Burn injury resulted in depressed chemotaxis compared with sham or sham/G-CSF-treated animals (p less than 0.05). Administration of rhG-CSF to burned animals resulted in a level of neutrophil chemotaxis comparable with that in control animals. The presence of a burn wound infection caused no further impairment of chemotaxis. Administration of rhG-CSF to animals with a burn wound infection resulted in improved chemotaxis compared with sham, burned, and burned/infected animals. The beneficial effect of G-CSF following burn wound infections from this and previous studies appears to be a combination of expanded numbers of myeloid elements and preservation of their function.

Granulocyte Colony-Stimulating Factor Enhances the Phagocytic and Bactericidal Activity of Normal and Defective Human Neutrophils

Granulocyte colony-stimulating factor (G-CSF) stimulates proliferation of myeloid cells and may be a valuable adjunct in prevention and treatment of neutropenia-associated infections. Neutrophil (PMNL) phagocytic and microbicidal functions against Staphylococcus aureus and Candida albicans blastoconidia were therefore evaluated. Bacterial phagocytosis and bactericidal activity were significantly enhanced by approximately 50%-70% after preincubation of normal PMNL with G-CSF in concentrations of 1000-4000 units/ml for 10 min at 37 degrees C. G-CSF in similar concentrations enhanced the defective bactericidal activity of PMNL from HIV-1-infected patients by approximately 70%-150% and reached the baseline control PMNL killing. However, G-CSF enhanced neither phagocytosis nor fungicidal activity of normal PMNL against C. albicans blastoconidia. These data demonstrate that G-CSF enhances the antibacterial but not the antifungal activities of human PMNL in vitro and also improves the defective PMNL bactericidal activity of HIV-1-infected patients.

Neutrophil function and pyogenic infections in bone marrow transplant recipients

In a consecutive entry trial, the incidence and time course of decreased neutrophil function was assessed in 20 patients treated with allogeneic bone marrow transplantation (BMT). The aim of the study was to assess the prognostic value of low neutrophil function for late pyogenic infections. Chemotaxis, superoxide production, and phagocytic- bactericidal activity were studied before and 2, 6, 9, and 12 months after BMT. Skin window migration was quantitatively assessed 2 months after BMT. Infectious complications were recorded prospectively with preset criteria during 1 year. Six of the 20 leukemic patients had defective neutrophil function before BMT. Two months after BMT all 10 patients with greater than stage II graft-versus-host disease (GVHD), and 6 of 10 patients with less than or equal to stage II GVHD had at least one decreased function. At this time, patients with subsequent pyogenic infections had lower chemotaxis (P less than .05), phagocytic- bactericidal activity (P less than .005), and superoxide production (P less than .025) than those without. Defective skin window migration and combined defects were predictive for late pyogenic infections. At 9 months all tests were normal in seven patients surviving without GVHD. In contrast, at 9 months three of three patients, and at 1 year two of three with chronic GVHD had still decreased neutrophil function. In conclusion, neutrophil function is frequently impaired during the first months after BMT. Combined neutrophil defects predispose to pyogenic infections and indicate the patient at risk.

Neutrophil Function and Pyogenic Infections in Bone Marrow Transplant Recipients

In a consecutive entry trial, the incidence and time course of decreased neutrophil function was assessed in 20 patients treated with allogeneic bone marrow transplantation (BMT). The aim of the study was to assess the prognostic value of low neutrophil function for late pyogenic infections. Chemotaxis, superoxide production, and phagocytic-bactericidal activity were studied before and 2, 6, 9, and 12 months after BMT. Skin window migration was quantitatively assessed 2 months after BMT. Infectious complications were recorded prospectively with preset criteria during 1 year. Six of the 20 leukemic patients had defective neutrophil function before BMT. Two months after BMT all 10 patients with greater than stage II graft-versus-host disease (GVHD), and 6 of 10 patients with less than or equal to stage II GVHD had at least one decreased function. At this time, patients with subsequent pyogenic infections had lower chemotaxis (P less than .05), phagocytic-bactericidal activity (P less than .005), and superoxide production (P less than .025) than those without. Defective skin window migration and combined defects were predictive for late pyogenic infections. At 9 months all tests were normal in seven patients surviving without GVHD. In contrast, at 9 months three of three patients, and at 1 year two of three with chronic GVHD had still decreased neutrophil function. In conclusion, neutrophil function is frequently impaired during the first months after BMT. Combined neutrophil defects predispose to pyogenic infections and indicate the patient at risk.

Defects in Neutrophils: An Overview

Neutrophils are the host's first line of defense against many pathogenic bacteria and fungi. Disorders of neutrophil function are often suggested by recurrent cutaneous, periodontal, respiratory, or soft tissue infections. In this review, we summarize the current understanding of neutrophil function, provide an update of recent developments in the field, and outline an approach to diagnosis and management of the major congenital disorders of neutrophils.

The Use of Hematopoietic Growth Factors in HIV Infection and AIDS-Related Malignancies

Human immunodeficiency virus (HIV) infection is associated with multiple defects in immune regulation and hematopoiesis. These defects include decreased proliferation of hematopoietic progenitor cells and increased destruction of mature cells. There are also disturbances of regulatory cytokines. As a result, hematopoietic cytopenias are common and the tolerance of myelosuppressive therapy is poor. One successful approach to the management of these clinical problems is the use of hematopoietic growth factors. To date, three agents have been studied in patients with HIV infection. In a Phase I trial, granulocyte macrophage-colony stimulating factor (GM-CSF) corrected leukopenia and pre-existing neutrophil defects in patients with HIV infection. In uncontrolled trials, GM-CSF also appears to reduce toxicity from zidovudine, ganciclovir, alpha-interferon, and antineoplastic therapy. In a placebo-controlled trial, erythropoietin (EPO) decreased transfusion requirements and corrected anemia in the majority of patients receiving zidovudine. In a Phase I/II trial, granulocyte colony-stimulating factor (G-CSF) also corrected leukopenia and neutrophil defects in patients with AIDS without altering HIV expression. Combined G-CSF and EPO treatment corrected both anemia and leukopenia and reduced zidovudine toxicity. New combinations of hematopoietic stimulants are being used to decrease the toxicity from cytotoxic chemotherapy in the treatment of AIDS-related malignancies. Future treatments with other recombinant cytokines may result in both reduction in myelosuppression from drug therapy and, possibly, reconstitution of the immune and hematopoietic systems of HIV-infected patients.

Abnormal Neutrophil Chemotaxis after Successful Bone Marrow Transplantation.

Twenty patients with self-sustaining hematopoiesis were evaluated for neutrophil functions and bone marrow histology 7 to 34 months after bone marrow transplantation (BMT) (7 allogeneic, 13 autologous) performed for acute leukemia in complete remission (11 patients), Hodgkin's lymphoma (2 patients), chronic myeloid leukemia (6 patients) or severe aplastic anemia (1 patient). The chemotactic response toward zymosan-treated serum was severely depressed (<35% of normal) in peripheral neutrophils of 11 patients (2 allogeneic and 9 autologous BMT) and moderately defective (35-70% of normal) in 5 others (2 allogeneic and 3 autologous BMT). On the other hand, phagocytic activity, activation of the metabolic burst and surface expression of CD11/CD18 molecules were within normal limits or moderately increased. The chemotactic defect was independent of age, sex, conditioning regimen and the time period after marrow infusion. The incidence of defective chemotaxis was much greater in patients receiving an autologous BMT (92% of the patients) than in those who had an allogeneic BMT (57% of the patients). Simultaneous bone marrow biopsy studies showed significant stromal alterations in most of our patients; since the bone marrow microenvironment plays an essential role in the process of blood cell formation and release, these observations suggest that defective neutrophil chemotaxis may well serve as a marker of abnormal post-transplant hematopoiesis.

Antibodies Directed to the Chemotactic Factor Receptor Detect Differences Between Chemotactically Normal and Defective Neutrophils From LJP Patients

Localized juvenile periodontitis (LJP) is a progressively destructive infection of the supporting tissues of the teeth, primarily affecting adolescents. In this disease, patients' polymorphonuclear leukocytes (PMN) exhibit decreased chemotaxis (CTX) and decreased binding of the chemotactic peptide N-formyl-l-methionyl-l-leucyl-l-phenyl-alanine (FMLP) to specific receptors on the PMN surface. Since the FMLP receptor is involved in the activation of the PMN, and its subsequent response to chemotactic stimuli, a decrease in the chemotactic peptide receptor, as seen in LJP patients, is suspected to be a predisposing factor for this disease. To define differences in the FMLP receptor between CTX defective LJP patients and CTX normal donors, a battery of monoclonal antibodies reactive against the FMLP receptor was prepared. The FMLP receptor was affinity-purified, and was found to be comprised of two components, one of 68 kDa, and the other of 94 kDa. Only the 68 kDa component specifically bound a radioiodinated FMLP analogue in a photoaffinity experiment. Seven monoclonal antibodies were selected on the basis of their reactivity with the 68 kDa receptor component, and of these, 5 showed reduced binding against PMN from CTX defective LJP donors when compared to their reactivity against PMN from CTX normal subjects. Two of the 7 anti-68 kDa antibodies reacted with PMN from both sets of subjects at a comparable extent. Furthermore, the presence of 20 nmol of FMLP inhibited the binding of 5 of the anti-receptor antibodies to whole PMN, including one that showed no difference in binding between CTX normal and defective PMN, and 4 of the 5 that did show such difference.(ABSTRACT TRUNCATED AT 250 WORDS)

3 Neutrophil function tests

The complexity of the neutrophil response to inflammation creates many difficulties for the study of neutrophil function in vitro. The environment in which a neutrophil is placed can have marked effects upon a variety of cellular functions. Quantitative tests of neutrophil function present problems not only with assay design but also in the isolation of cells from peripheral blood without disturbing their normal physiology. It is desirable to isolate neutrophils from other leukocytes because soluble factors released by other cells can influence neutrophil function, and other cells may interfere with functional assays; for example, monocytes will phagocytose opsonized particles and eosinophils contain a potent peroxidase. Attention to physical parameters such as temperature, pH or osmolarity, and rigorous exclusion of endotoxin, permits neutrophils to be isolated in a resting state. Subsequent function tests must be selected with an understanding of normal neutrophil physiology and applied with an awareness of any associated technical problems. The investigation of abnormal neutrophil responses may necessitate the screening of several tests of function; for example, defective neutrophil killing may be the result of abnormal chemotaxis, phagocytosis or degranulation. Which tests are appropriate will depend upon the questions to be answered and on the quantity of cells available for study.

Complement Deficiency and Neutrophil Dysfunction as Risk Factors for Bacterial Infection in Newborns and the Role of Granulocyte Transfusion in Therapy

The similarity in the susceptibility to bacterial infections of newborns and older patients with complement deficiencies, neutropenia, or neutrophil function defects has suggested that neutrophils and/or complement might also be defective in newborns. Although no individual element of the phagocytic host defense system is severely deficient, several partial deficiencies have been identified. These involve important amplification pathways of complement and neutrophil activation and may combine to cause significant decreases in phagocyte activity at sites of infection. Because of decreased specific antibody, initial activation of the classical complement pathway is decreased. Low levels of C3 and factor B decrease amplification by the alternative pathway and result in marked decreases in opsonization and generation of chemotactic activity from C5. There are also quantitative and qualitative neutrophil defects. The recent observations that newborns' neutrophils are relatively deficient in membrane expression of their major adherence protein/C3bi receptor help explain the decreased mobility and phagocytic activity of these cells. Thus, several partial deficiencies combine to cause severe impairments in delivery of neutrophils to sites of infection and contribute to the increased susceptibility of the newborn to infection.

An Acquired Chemotactic Defect in Neutrophils from Patients Receiving Interleukin-2 Immunotherapy

Bacterial sepsis is a frequent complication in patients with cancer who are receiving high doses of interleukin-2. We evaluated the function of neutrophils from such patients to determine whether there was any abnormality in this form of host defense. Before interleukin-2 therapy, neutrophils from 31 patients with metastatic cancer were normal in assays of random migration and chemotaxis. Superoxide production, phagocytosis, secretion of granule proteins, and bactericidal activity were also normal. Neutrophils from the patients near the end of the first course of interleukin-2 had severely impaired chemotaxis in response to a formylated peptide stimulus (mean [+/- SEM], 49.6 +/- 7.4 percent of base line; P less than 0.001). The detect in chemotaxis improved 5 to 10 days after patients completed the first course of interleukin-2 therapy but recurred toward the end of the second course of such therapy (35.3 +/- 6.9 percent of base line; P less than 0.001). The chemotactic response to a second stimulus (zymosan-activated serum) was also abnormal, but random migration, superoxide production, bactericidal activity, and the secretion of neutrophil granule constituents remained normal or increased throughout treatment with interleukin-2. We conclude that patients who receive interleukin-2 immunotherapy acquire an acute, profound, and reversible defect in neutrophil chemotaxis that may contribute to the high morbidity resulting from bacterial infections in these patients.