[Immunostaging (author's transl)].
This survey covers the problems of immunologic monitoring of patients and the spectrum of methods of diagnosing various types of immunopathological reactions.
Allergens↗
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Results for “Monitoring, Immunologic”
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Neopterin production in SCID mice injected with human peripheral blood mononuclear cells.
Intraperitoneal transfer of peripheral blood mononuclear cells (PBMC) from human EBV+ donors into severe combined immunodeficiency (SCID) mice is a suitable model for studying some aspects of lymphomagenesis and immune activation. Neopterin is a soluble immune marker which was found to be a useful indicator for immune activation processes in humans, e.g. to monitor immunological complications in allograft recipients or to predict prognosis in HIV-infected individuals. In contrast, this pteridine compound is normally synthesized in murine organism in only very low amounts. The measurement of neopterin concentrations in serum and urine should be feasible in SCID mice reconstituted with human PBMC. In this study, we examined the usability of this experimental model for monitoring human T cell activation by neopterin measurements. The production of neopterin by SCID mice after injection of freshly isolated human PBMC, purified B or T cells and cultured Epstein-Barr virus (EBV)+ lymphoblastoid cells (LCL) was determined. It was found that neopterin can be detected early after injecting SCID mice with PBMC, whereas injection of purified human T or B cells did not result in neopterin production. Highest neopterin levels were detected in mice treated with LCL cells when developing lymphoma. We discuss the possible sources of neopterin along this process and its usefulness in this model.
Animals↗
Immune monitoring protocol for patients with carcinoma of the head and neck. Preliminary report.
Numerous investigators have observed a depression of cell-mediated immunity in patients with carcinoma of the head and neck using a variety of in vitro and in vivo assays. This report presents the data obtained when a group of head and neck cancer patients were evaluated for reactivity in an in vitro lymphocyte blastogenesis assay using polyclonal mitogens and specific antigens, numbers of peripheral blood T-lymphocytes, and levels of circulating immune complexes. Such an immunological monitoring protocol revealed a depressed reactivity of the cancer patients in the lymphocyte blastogenesis assay when compared to normal age-matched controls. We also observed that 75% of these patients had circulating soluble immune complexes in their sera before and after therapy. These preliminary data indicate that further research is needed to examine the potential role of soluble immune complexes in modulating the host's immune response.
Adult↗
Vaccination of patients with metastatic renal cell carcinoma with autologous dendritic cells pulsed with autologous tumor antigens in combination with interleukin-2: a phase 1 study.
Dendritic cells (DC) have been recognized as the most potent antigen presenting cells (APC) of the immune system. We performed a phase 1 study in twelve patients with metastatic renal cell carcinoma (RCC) using autologous immature DC loaded with autologous tumorlysate (TuLy) as a vaccine based on our earlier in vitro observations that such DC can activate tumor-specific cytotoxic T-lymphocytes. The treatment was combined with low-dose interleukin (IL)-2, as this has shown benefit in DC-based therapies. Patients received three intradermal vaccinations at two weekly intervals, and, after each vaccination, IL-2 was administered for 5 consecutive days. In six patients, keyhole-limpet hemocyanin (KLH) was added to the DC culture for immunologic monitoring purposes. In general, DC phenotype was CD14(low), CD86(high), CD40(high), CD80(low), and CD83(low). We noticed that the number of CD14+ cultured DC increased during treatment. Nevertheless, ovalbumin uptake remained high, underlining that these cells were still functional immature DC. The vaccine was able to elicit cellular anti-KLH responses, emphasizing the ability of the injected DC to mount an immunologic response. However, proliferative responses against TuLy were not detected, and humoral responses against TuLy or KLH were absent. Objective clinical responses were not observed, but extended stable disease was noted. The absence of cellular, humoral, or clinical antitumor responses suggests that the vaccination strategy with immature DC has little benefit for patients with advanced RCC. Nevertheless, this study shows the feasibility of a completely autologous DC and tissue culture methodology for the generation of TuLy pulsed DC.
Adjuvants, Immunologic↗
Viral escape and T-cell immunity during ganciclovir treatment of cytomegalovirus infection: case report of a pancreatico-renal transplant recipient.
BACKGROUND: Pancreas-kidney transplant recipients are at high risk for cytomegalovirus (CMV) disease despite prophylactic ganciclovir therapy. Because the impact of antiviral therapy on anti-CMV immune reactions is unknown, CMV-specific T-cell subsets in primary and recurrent CMV infection were analyzed in a pancreas-kidney transplant case study. METHODS: Major histocompatibility complex class I tetramers were used to detect peripheral CMV pp65-specific CD8 T cells. Intracellular cytokine staining was used to determine the frequency of CMV-specific CD4 T cells. Conventional virologic parameters and routine laboratory parameters were monitored. For ganciclovir resistance testing, CMV-UL97 genotyping was performed. RESULTS: Despite prophylactic ganciclovir therapy, primary CMV infection induced in vivo expansion of activated CMV-specific CD8 T cells. Interestingly, viral dissemination during recurrent CMV disease was a result of partially ganciclovir-resistant CMV. Recovery after discontinued ganciclovir treatment was associated with the expansion of CMV-specific CD4 T cells. CONCLUSION: Immunologic monitoring may contribute to clinical management of recurrent CMV disease.
Antiviral Agents↗
Durable carcinoembryonic antigen (CEA)-specific humoral and cellular immune responses in colorectal carcinoma patients vaccinated with recombinant CEA and granulocyte/macrophage colony-stimulating factor.
PURPOSE: Previous studies have indicated that carcinoembryonic antigen (CEA) might be a suitable immunotherapeutic target in colorectal carcinoma (CRC). The aim of the present study was to analyze the immunological and clinical effects of vaccination with CEA together with the adjuvant granulocyte/macrophage colony-stimulating factor (GM-CSF). EXPERIMENTAL DESIGN: Twenty-four resected CRC patients without macroscopic disease were immunized seven times with recombinant CEA at four different dose levels over a 12-month period. Half of the patients received GM-CSF (80 microg/day for 4 consecutive days) at each immunization. Patients were monitored immunologically for 36 months and clinically for 76 months. T-cell response was evaluated by a [(3)H]thymidine incorporation assay, and IgG response was determined by ELISA. RESULTS: Minor local side effects were common. All 12 patients (100%) in the GM-CSF group developed a CEA-specific T-cell as well as an IgG response. The corresponding figures in the CEA alone group were 9 of 12 (75%) and 8 of 12 (66%), respectively. GM-CSF significantly augmented the amplitude of the T-cell response and the IgG titers. No dose-response relationship was noted. The immune responses at 12 months persisted 24 months after the last vaccination. Anti-CEA IgG titers were associated with increased survival (P < 0.05), whereas standard prognostic factors had no relationship, with the exception of serum CEA value. CONCLUSIONS: Vaccination with recombinant CEA and GM-CSF appears to be a nontoxic regimen inducing potent and durable antigen-specific IgG and T-cell response. The results of this study justify more extensive trials with recombinant CEA protein for immunotherapy of CRC.
Adult↗
Immunological and plasma protein changes in cancer patients following a single plasmapheresis.
Serial serum protein determinations and immunological monitoring were performed prior to and following a single 4 to 5 liter plasma exchange in 10 patients with disseminated cancer. The most consistent changes were observed for two initially elevated alpha globulins, acid glycoprotein and haptoglobin, which declined rapidly in all patients 1 hour after plasmapheresis and began to rise again as early as 24 hours post-plasmapheresis to reach initial levels by 72 hours. Among the immunological parameters T and B cell counts, and phytohemaglutinin-induced lymphocyte transformation showed little change. In 4 out of 10 patients C3 levels dropped at 1 hour post-plasmapheresis and continued to decline to 24 hours, suggesting that consumption of C3 possibly by macrophages may have occurred. In view of our earlier reports that repeated plasmapheresis induced partial tumor regressions in patients with disseminated cancer and that these regressions may have been related to depletion of immunosuppressive serum proteins, it is suggested that to maintain levels of these rapidly renewed proteins at a minimum for as long as possible, it is most appropriate to perform plasmapheresis every 48 hours rather than every 72 or 96 hours as was the case in the earlier study.
Adult↗
Restoration of expression of signal-transduction molecules in lymphocytes from patients with metastatic renal cell cancer after combination immunotherapy.
A decrease in lymphocyte signal-transduction molecules, described in cancer patients and patients with chronic infectious diseases, has been proposed as a possible mechanism leading to an impaired immune response in cancer patients. Here we report the effects of combination immunotherapy on the levels of T cell receptor zeta chain and p56lck tyrosine kinase in a retrospective study of cryopreserved lymphocytes from 26 metastatic renal cell carcinoma patients treated with high-dose interleukin-2 (IL-2), interferon alpha (IFNalpha) and ex vivo IL-2-activated lymphocytes. Of the 26 patients, 12 were responders (5 complete and 7 partial) and 14 were non-responders (6 stable and 8 with progressive disease). Prior to treatment, 21 of 26 patients (81%) and 13 of 21 patients (62%) respectively expressed zeta chain and p56lck at less than 50% of the levels observed in healthy controls. During therapy, this low zeta chain and p56lck expression increased to at least 50% of normal in 13 of the 21 patients (62%) and in 6 of the 13 patients (46%) respectively; in the remaining patients expression levels remained at 50% of normal or more, or declined. Although, in this limited study, pretreatment levels of and p56lck did not show significant correlation with antitumor response, 4 of 5 patients that achieved a complete response (80%) corrected both zeta chain and p56lck levels to at least 50% of normal, while restoration of both signal-transduction molecules to such levels was only observed in 3 of 7 partial responders (43%), 1 of 5 patients with stable disease (20%) and 2 of 7 patients with progressive disease (29%). Thus, these results suggest that analysis of changes in signal-transduction molecules may a be useful tool for immunological monitoring of patients throughout immunotherapy, and could provide important information for designing new clinical trials that restore impaired signal transduction while activating T cell responses.
Antineoplastic Agents↗
Immunological and clinical effects of intramuscular rIFN alpha-2a and low dose subcutaneous rIL-2 in patients with advanced malignant melanoma.
Fifteen patients with tumour recurrence following radical surgical excision of malignant melanoma were treated with a combination of interferon alpha-2a (rIFN alpha-2a) and interleukin-2 (rIL-2). Immunological monitoring (performed prior to therapy and on days 7, 21, and 28, of each course of treatment) showed significant changes of several parameters after rIFN alpha-2a and rIL-2 administration. A significant increase in cells expressing CD16 (cells bearing Fc receptor), CD25 (cells bearing IL-2 receptor), and CD56 (NK cells, activated lymphocytes), as well in levels of soluble IL-2 receptor, beta 2-microglobulin and neopterin was observed. Immunological changes were closely related to the injection of the biological agent and were more relevant during the first than the second cycle of treatment. rIFN alpha-2a and rIL-2 exerted a clear synergistic activity on the same immunological parameters. No major response was seen with the present approach: four subjects showed rapid progression of decrease during the first month of therapy, while of 11 patients who completed two courses of treatment, only five were considered in stable disease. In conclusion, our results suggest that a combination of rIFN alpha-2a and rIL-2, at dosages and schedules, used in this trial, was well-tolerated and immunologically active, but was clinically ineffective in the management of advanced melanoma.
Adult↗
Phase I clinical and pharmacokinetic trial of flavone acetic acid.
Flavone acetic acid is a synthetic benzopyrone derivative with an unknown mechanism of action. Thirty-eight patients (30 men and 8 women) were treated once a week for 4 weeks every 5 weeks with doses of flavone acetic acid ranging from 0.33 to 12.5 g/m2. At doses less than or equal to 3.9 g/m2, the drug was administered intravenously over 1 hour; at doses greater than or equal to 5.28 g/m2, the infusion period was lengthened to 6 hours. Treatment of all patients included hydration before and after treatment and alkalization to maintain urine pH at greater than or equal to 6.5. A dose-limiting toxic effect was hypotension at 10 g/m2. Pharmacokinetic studies revealed linear behavior in the eight patients studied, beginning at 3.9 g/m2. Peak plasma levels ranged from 125 to 630 micrograms/mL, with a mean terminal half-life of 22.4 hours. Immunologic monitoring was performed in three patients at 10 g/m2. A transient increase in CD16- and/or Leu-19-positive cells was noted in all three patients. In one patient, this increase correlated with a 10-fold increase in K562 cell killing. There were no objective tumor responses seen in this trial. The recommended phase II dose on this schedule is 8 g/m2. Further studies to elucidate the drug's mechanism of action and to define its immunologic properties are recommended.
Adult↗
Cytokines and transplantation: a clinical perspective.
Cytokines are endogenous small peptides that regulate cell growth and proliferation. In allogeneic transplantation, they function as critical immunologic mediators. Allograft rejection is dependent on interactions between antigen-presenting cells, T lymphocytes, accessory molecules, and proinflammatory cytokines (interleukins-1, -2, and -6; interferon-gamma; and tumor necrosis factors). Alternatively, other cytokines (interleukins-4, -5, and -10; transforming growth factor-beta) may suppress allograft rejection. Observation and manipulation of cytokine responses are an essential component of the immunopharmacology and clinical management of transplant recipients. Specific areas of interest include immunologic monitoring, pharmacologic immunosuppression, monoclonal antibody development, induction of tolerance, and the OKT3-related cytokine release syndrome. This review explores the impact of advances in cytokine physiology and biotechnology on clinical transplantation.
Animals↗
Human tumour immunology.
Many human cancer cells appear to differ from their normal counterparts in ways that are recognisable by the immune system of the host or patient. The specificities of these differences, however, and the nature, extent and significance of the most responses to them are often not very clear. Disturbances of the immune system generally contribute little to the occurrence, progression and clinical features of common malignant diseases. The present value of immunological monitoring of cancer patients is rather limited. Immunotherapy remains an experimental mode of treatment, the results of which are often disappointing. Current studies of the host-tumour relationship in experimental animals and man suggest, however, that a wholly pessimistic view is not justified.
Animals↗
[Does an immune reactivity to human laryngeal cancer exist?].
Authors reconsider the present state of knowledge about immunology of laryngeal cancer. Authors, besides, analyse, in a critical way, problems concerning immunological monitoring of patients bearing solid carcinomas. They conclude that, up to date, it is impossible to have a biological test which can concretely show the patient's immune state.
Antigen-Antibody Reactions↗
Cyclosporine measurement by FPIA, PC-RIA, and HPLC following liver transplantation.
The factors affecting CyA dosing and kinetics in LT patients are complex, and have been thoroughly investigated and reviewed. Plasma or WB CyA concentration monitoring remains the best method presently available for adjusting CyA dosage in LT patients in a timely manner. The availability of an FPIA assay for CyA has produced rapid drug analysis for transplant patient monitoring, but adds additional factors that must be considered in interpreting CyA concentrations. Liver dysfunction may disproportionately elevate CyA plasma or blood levels when analyzed by FPIA in relation to PC-RIA or HPLC, and adjustment of the therapeutic range or analysis by a more specific assay method may be necessary for dosage adjustment in these patients. The availability of a more specific antibody in an FPIA assay may avert these problems, as would the development of immunologic monitoring techniques that provide a global assessment of immune suppression produced by increasingly complex immunosuppressive regimens in LT patients.
Bilirubin↗
[Simultaneous double fluorescence flow cytometry of lysed whole blood for prenatal diagnosis of combined immunodeficiency].
Simultaneous two-color flow cytometry of lysed whole blood allows the collection of maximal information from minimal blood volumes. This method was used for prenatal diagnosis of severe combined immunodeficiency by analysis of fetal blood. The data demonstrate that flow cytometry of lysed whole blood provides a reliable tool for prenatal diagnosis of certain immunodeficiencies. Moreover, the method described seems highly suitable for immunological monitoring of preterm infants and newborns. To enable the diagnosis of more subtle immunodeficiency states in these patients, however, valid normal values for all investigated parameters need to be defined first for the respective age/weight groups.
Female↗
Alterations in immunologic measurements in patients experiencing early hepatic allograft rejection.
We compared lymphocyte subsets, the T4:T8 ratio, and assays of lymphocyte function in 11 recipients of hepatic allografts who showed signs of early graft rejection (less than 3 weeks after transplant) with 13 patients who had no evidence of graft rejection. Both patient groups had similar values for lymphocyte subsets, lymphocyte transformation in the presence of phytohemagglutinin, and in vitro immunoglobulin synthesis prior to allografting. Nonrejectors had a decline in both T3 and T4 cells one week after transplant. Those who had evidence of graft rejection did not show a significant decline in either of these T cell subsets. The T4:T8 ratio declined in 11/13 nonrejectors in the week after transplant but in only 4/11 rejectors (P less than 0.05). Monitoring immunologic markers in blood may represent a means of determining which subjects are at greatest risk for developing early hepatic allograft rejection.
Antigens, Differentiation, T-Lymphocyte↗
Clinical and experimental aspects of renal allograft rejection.
The pathophysiology, differential diagnosis, and clinical management of renal allograft rejection is reviewed. Recent data have revealed the discriminant biochemical and functional attributes of Class I (HLA-A,B, and C) and Class II (HLA-DR) major transplantation antigens. Graft rejection is an intricate process in which several cytodestructive mechanisms may coexist. The role of donor-specific and nonspecific immunologic monitoring tests in patient management is reviewed. Acute cellular rejection is usually readily reversed by high dose corticosteroid therapy while chronic humoral rejection is refractory to such treatment. Treatment of steroid-resistant rejection episodes by plasmapheresis/antilymphocyte globulin is under investigation.
Antibody-Dependent Cell Cytotoxicity↗
Studies on the survival of simultaneous canine renal and segmental pancreatic allografts.
Prolonged survival of the vascularized free-draining intraperitoneal pancreatic segmental allografts (FDPS) has been observed previously in immunosuppressed beagle littermates matched for low mixed lymphocyte culture (MLC) reactivity. When rejection (hyperglycemia) did occur, it was abrupt, unpredictable, and irreversible. This contrasts with renal allograft rejection in which elevations of serum creatinine are reversible with increased immunosuppression. In the present experiments, low MLC-reactive littermate pairs underwent simultaneous transplantation of kidney and FDPS allografts from the same donor. Increases in serum creatinine from 0.5 mg/dl to 1.5 mg/dl (renal rejection) occurred 4 to 5 days after transplantation (mean = 20.5 +/- 4.1) and preceded the onset of hyperglycemia by 6 to 22 days (mean = 1.06 +/- 4.6) in nonimmunosuppressed animals. At the onset of kidney rejection but before hyperglycemia developed, renal allograft biopsies revealed generalized mononuclear infiltration, while FDPS biopsies showed diffuse interstitial infiltration, but islets of Langerhans appeared to be spared. Treatment intervention with azathioprine and corticosteroids at the time of creatinine elevation prevented the onset of hyperglycemia from 46 to greater than 260 days in four of nine animals. Biopsies after 2 weeks of therapy showed resolution of the lymphoid infiltrates in the kidney and limitation of infiltrates to perivascular areas in the FDPS allografts. Immunological monitoring of peripheral blood lymphocyte function demonstrated the development of positive in vitro cell-mediated lymphocytoxicity shortly before the onset of hyperglycemia but only after creatinine elevation was well established and biopsies revealed evidence of rejection in both the renal and FDPS allografts.
Animals↗