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P T Schellekens

Publications and source records attributed to P T Schellekens.

At least 19 recordsLinked to original sources
PubMed1992

Monoclonal antibodies in renal transplantation: a review.

OKT3 is the first anti-CD3 monoclonal antibody available for treatment in humans. Over the last few years it has proven to be a very powerful immunosuppressive agent in renal transplantation. Clinical studies have shown that OKT3 is superior to high-dose steroids as first-line treatment for acute renal allograft rejection. Furthermore, it is comparable to antithymocyte globulin (ATG) in treating steroid-resistant rejection and is also effective as rescue treatment in ATG- and antilymphocyte globulin-(ALG-) resistant rejection. Despite its excellent rejection-reversal rate, OKT3 treatment is followed by a substantial percentage of re-rejections, most of which respond well to steroids. In the early post-transplantation period, a prophylactic course of OKT3 is very effective in preventing acute rejections, and in this respect it is probably equivalent to ATG. Indirect evidence exists that a prophylactic course of OKT3 may be beneficial in immunologically high-risk patients and in patients with delayed graft function. However, more clinical studies are required to answer the question whether OKT3 should be given as induction treatment, as first-line treatment, or as rescue treatment. To answer this question, the side effects of OKT3 should also be taken into account. First-dose-related side effects, although frequent and disturbing, are usually transient and seldom life-threatening, provided overhydration has been corrected and steroids have been given before the first administration. These side effects are attributed to the release of cytokines as a result of T-cell activation or lysis. After exposure of patients to OKT3 an increased incidence of infections and malignancies has been reported. However, it is not yet clear whether this is due to OKT3 as such, or whether it merely reflects the total burden of immunosuppression. Xeno-sensitization represents an important limitation to OKT3 treatment, although a second or third course can still be effective in patients with low antibody titers. The precise immunosuppressive mechanism of anti-CD3 monoclonal antibodies is yet unknown. Monitoring of patients treated with OKT3 revealed CD3 and/or T-cell antigen receptor depletion and immunological incompetence of remaining T cells. More clinical data are required to establish the correct dose and duration of OKT3 treatment. In conclusion, OKT3 is a powerful immunosuppressive agent but its real value in renal transplantation remains to be determined. A practical approach may be to reserve it for the treatment of steroid-resistant rejections.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1992

Viral phenotype and immune response in primary human immunodeficiency virus type 1 infection.

Nineteen individuals were studied for virologic and immunologic events during primary human immunodeficiency virus type 1 (HIV-1) infection. In 16 individuals only non-syncytium-inducing (NSI) isolates were detected; syncytium-inducing (SI) isolates were obtained from 3. Studies of transmitter-recipient pairs indicated that both NSI variants and SI variants were transmitted and that SI variants may be suppressed in the recipient. CD4+ T cells remained in the normal range in 15 of 16 individuals with NSI isolates but rapidly declined in all 3 individuals with SI variants, 1 of whom was treated with zidovudine. The most marked increase in CD8+ T cells and activated CD8+ T cells was observed in individuals with the most pronounced clinical signs of acute HIV-1 infection. Activated CD8+ T cells were only transiently elevated in individuals with SI variants, suggesting that an impaired cellular anti-HIV-1 immune response plays a role in the rapid progression to AIDS.

CD4-Positive T-Lymphocytes↗
PubMed1992

Biphasic rate of CD4+ cell count decline during progression to AIDS correlates with HIV-1 phenotype.

OBJECTIVE: To determine the kinetics of decline of CD4+ lymphocytes in HIV-1-infected asymptomatic homosexual men. METHODS: CD4+ lymphocytes were enumerated in a cohort of 187 HIV-1-infected initially asymptomatic homosexual men seen at 3-month intervals over 5 years. During follow-up, 45 men progressed to AIDS (excluding cases presenting with Kaposi's sarcoma). Correlation between rate of CD4+ cell decline and presence of a particular HIV-1 biological phenotype was analysed in 43 participants. RESULTS: CD4+ cell counts declined slowly and continuously in HIV-1-seropositive men who remained asymptomatic during follow-up. A biphasic CD4+ cell count decline was observed in the group who developed AIDS: the decline was slow and steady (5.6 x 10(6)/l per month, similar to that observed in the asymptomatic group) until 18 months before AIDS diagnosis, but became three to five times faster thereafter. Rapid CD4+ cell decline was significantly related to syncytium-inducing, fast-replicating HIV-1 isolates; during the period of slow and steady CD4+ cell count decline, non-syncytium-inducing isolates were predominant. CONCLUSIONS: At an average of 18 months preceding AIDS diagnosis, a three to fivefold increase in the rate of loss of CD4+ lymphocytes occurs, and may be related to the appearance of a more virulent HIV-1 phenotype.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Reappearance of vanished bile ducts.

A 36-year-old Surinam woman with a severe form of toxic epidermal necrolysis of unknown origin is presented. Skin lesions healed gradually without scarring within 3 to 4 weeks, but eye lesions progressed to symblepharon and corneal opacification, resulting in almost complete blindness. In addition, toxic epidermal necrolysis was associated with severe intrahepatic cholestasis caused by vanished bile duct syndrome; viral hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis were excluded. After about six months, intrahepatic chole-stasis improved spontaneously and a third liver biopsy taken after 51 weeks of illness revealed that the bile ducts had reappeared. At present, the patient is relatively well, with no jaundice, although parameters of cholestasis are still elevated: Alkaline phosphatase three times, and gamma GT thirty times the normal values. This sequence of events has to our knowledge never been reported in the literature.

Adult↗
PubMed1991

Frequent injecting impairs lymphocyte reactivity in HIV-positive and HIV-negative drug users.

To investigate whether drug use affected immunological parameters, we conducted a cross-sectional study of 321 drug users. Absolute numbers of CD4+ lymphocytes and the T-cell reactivity were lower in HIV-positive than in HIV-negative people. The functional capacity of the T-cell system as measured after stimulation with a monoclonal antibody directed against CD3 was found to be strongly associated with the frequency of injecting, while no relationship was found between the frequency of injecting and the total number of lymphocytes or T-cell subsets. HIV-negative and HIV-positive drug users who had injected a mean of three times a day in the preceding 4-6 months had a T-cell reactivity which was 40-50% lower compared with seronegative and with seropositive drug users who had not injected in the preceding months. We conclude that lymphocyte reactivity is depressed by frequent injecting in HIV-negative and HIV-positive drug users.

Adult↗
PubMed1991

Differences in clinical course in zidovudine-treated asymptomatic HIV-infected men associated with T-cell function at intake.

Declining CD4+ T-cell numbers and anti-CD3-induced T-cell responsiveness are prognostic markers for progression of HIV infection. We investigated the effect of long-term (2-year) zidovudine treatment on these immunological markers in a group of nine asymptomatic p24-antigenaemic men, five of whom progressed to AIDS. A group of 10 untreated HIV-infected men, five of whom progressed to AIDS, was studied as a control. At intake, 1 year before the start of treatment, CD4+ T-cell numbers in the groups were not significantly different. However, at that time progressors already exhibited an extremely low anti-CD3-induced T-cell responsiveness compared with non-progressors. In all people T-cell responsiveness and the number of CD4+ T-cells had improved 6 months after the start of zidovudine treatment. However, CD4+ T-cell numbers were not persistently elevated, and restoration of T-cell responsiveness was of only short duration. Our results show that zidovudine treatment in the asymptomatic phase of HIV infection did not result in a sustained improvement in T-cell function. Furthermore, they suggest that differences in clinical course among zidovudine-treated asymptomatics may be caused by heterogeneity of this group with respect to T-cell functional capacity at the start of treatment.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Immunological and virological markers in individuals progressing from seroconversion to AIDS.

Six men were selected from a large cohort of homosexual men participating in a study on HIV infection that was followed from seroconversion to AIDS. The patients were studied retrospectively for immunological functions of T cells, T-cell subset distribution and biological phenotype of HIV. A severe decrease in anti-CD3 monoclonal antibody (MAb)-induced T-cell proliferation at seroconversion was observed in two out of six men. After this acute phase, CD4+ T-cell numbers were in the normal range in the early asymptomatic period; the proliferative response was subnormal, whereas the capacity to generate cytotoxic T cells (CTL) was normal. From seroconversion on, CD4+CD29+ memory T-cell numbers were decreased to approximately 50% of normal values, which may contribute to loss of T-cell reactivity. In the asymptomatic phase only slow-replicating non-syncytium-inducing HIV variants were observed. The T-cell proliferative response further declined with the depletion of naive CD4+ CD45RA+ T cells and CD4+ T-cell numbers started to decline. This second decrease in T-cell function coincided with the emergence of more rapidly replicating, often (four out of six) syncytium-inducing variants. At diagnosis of AIDS, T-cell proliferation and CD4+ T-cell numbers were extremely low in five out of six patients and CTL function had declined in three out of five individuals tested. Circulating CD8+ cells had gradually shifted to an immature CD38+CD28- phenotype. Our findings support the theory that HIV-induced immune dysfunction allows for the emergence of virulent HIV variants associated with CD4+ cell loss and disease.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Low T-cell responsiveness to activation via CD3/TCR is a prognostic marker for acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus-1 (HIV-1)-infected men.

In a cohort of 300 HIV-1-infected homosexual men, studied longitudinally, the prognostic value of T-cell proliferative responses for development of AIDS was analyzed. In 15 persons we observed that, at seroconversion, T-cell reactivity to anti-CD3 monoclonal antibody (Mab) and phytohemagglutinin (PHA) was decreased to 20 and 60% of the normal values, respectively. After seroconversion, within 3 months, the response to anti-CD3 Mab and PHA returned to 60 and 80%, respectively, of the normal magnitude and declined thereafter. To investigate whether low T-cell reactivity correlated with progression to AIDS, groups of progressors and nonprogressors were compared. In individuals who progressed to AIDS, already 12 months before diagnosis, responses to anti-CD3 Mab were virtually absent, whereas at that time CD4+ cell numbers and reactivity to horse anti-human lymphocyte serum and PHA were still comparable to values observed for nonprogressors and the asymptomatic population as a whole. In a disease-free survival analysis, low anti-CD3 Mab reactivity predicted progression to AIDS. Our findings demonstrate that low T-cell responsiveness to anti-CD3 Mab is an early marker of progression toward AIDS in HIV-1 infected individuals.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Pharmacodynamic modeling of lymphocytopenia and whole blood lymphocyte cultures in prednisolone-treated individuals.

In this study, we describe the time course of the influence of a single oral dose of prednisolone (10 mg) in man on the proliferative response of peripheral blood lymphocytes in whole blood. The data were fitted to an integrated pharmacokinetic-pharmacodynamic model, relating the plasma concentrations of prednisolone to its effect. The determination of prednisolone-induced lymphocytopenia and monocytopenia in vivo and the assessment of the influence of varying lymphocyte and monocyte numbers on proliferative responses in vitro enabled us to calculate the relative contributions of several prednisolone-induced effects to the diminished lymphoproliferative responses in whole blood after administration of prednisolone in vivo. We demonstrate that the decrease of the proliferative response in whole blood lymphocyte cultures stimulated with a monoclonal antibody directed against CD3 is mainly determined by the time course of the prednisolone-induced lymphocytopenia. The time course of the monocytopenia and the relative changes in the CD4+ and CD8+ T-cell subpopulations induced by prednisolone and the direct inhibitory effect of the changing plasma concentrations of the drug also contribute to the decrease of aCD3-stimulated whole blood lymphocyte cultures to some extent. The decrease of the proliferative response in whole blood lymphocyte cultures stimulated with a horse anti-human lymphocyte serum closely followed the time course of the lymphocytopenia induced by prednisolone. However, this response remained decreased for a longer period of time than could be expected on the basis of the prednisolone-induced lymphocytopenia in vivo. A possible mechanism which might explain this discrepancy between the prednisolone-induced effects in vivo and in vitro will be discussed.

Administration, Oral↗
PubMed1990

Long-term zidovudine treatment of asymptomatic HIV-1-infected subjects.

Eighteen asymptomatic men with persistent human immunodeficiency virus type 1 (HIV-1) p24 antigenemia were treated with zidovudine 250-500 mg (+/- acyclovir 800 mg) 6-hourly for 4-12 weeks, and thereafter with zidovudine 500 mg (+/- acyclovir 1600 mg) 12-hourly for 92 weeks. Six additional HIV-1 p24 antigenemic subjects were treated with zidovudine 500 mg 12-hourly for 76 weeks. Disease progression occurred in 4 subjects, despite sustained reduction of serum HIV-1 p24 antigen levels: Pneumocystis carinii pneumonia was diagnosed after 60, 80, 90 and 93 weeks, respectively. The median CD4+ cell count of these 4 men at study entry was 0.2 x 10(9)/l, and it declined to 0.07 x 10(9)/l at the moment AIDS was diagnosed. In 20 subjects no disease progression occurred. The median CD4+ cell count of these 20 men at study entry was 0.4 x 10(9)/l and it was 0.45 x 10(9)/l at the end of the study period. Median serum HIV-1 p24 antigen levels at the end of the study period were 42% lower than at study entry in these 20 subjects. In 5/20 men, an initial decline was followed by a rise in antigen levels to above pretreatment value. Treatment with zidovudine was well tolerated. Anemia caused symptoms in 3/24 men, but prolonged leucopenia or neutropenia did not occur. None developed clinical or convincing biochemical evidence of zidovudine-associated myopathy.

Acquired Immunodeficiency Syndrome↗
PubMed1990

The influence of prednisolone on the recirculation of peripheral blood lymphocytes in vivo.

In humans and in laboratory animals, administration of a single does of glucocorticosteroids induces a rapid and transient decrease in the numbers of peripheral blood lymphocytes through a redistribution of circulating lymphocytes. This lymphocytopenic effect is an important factor in the immunosuppressive capacity of corticosteroids. We have investigated whether the redistribution is due to an increased influx of circulating lymphocytes from the blood into the lymphoid organs or to a decreased efflux from the organs. Fluoresceinated lymphocytes were injected intravenously in unrestrained normal and prednisolone-treated rabbits and the distribution curves in the peripheral blood were analysed on the basis of a two-compartment model (known from pharmacokinetic studies). In this way, it is shown that the rapid fall in peripheral blood lymphocyte numbers induced by prednisolone is due to a decreased efflux of circulating lymphocytes from the lymphoid organs. In addition, it is demonstrated that prolonged infusion of prednisolone leads to an altered distribution pattern of the circulating lymphocytes among the organs.

Animals↗
PubMed1990

Functional and phenotypic evidence for a selective loss of memory T cells in asymptomatic human immunodeficiency virus-infected men.

In addition to a well-documented depletion of CD4+ T helper cells in later stages of human immunodeficiency virus (HIV) infection, evidence has been provided for a specific unresponsiveness to triggering either by specific antigen in the context of autologous major histocompatibility molecules (self + X) or anti-CD3 monoclonal antibodies (MAb) in both CD4 and CD8 cells from asymptomatic HIV-infected individuals. In the present study we analyzed this unresponsiveness using mitogenic antibodies to distinct T cell membrane receptors. T cells from HIV-infected men who had normal numbers of CD4+ T cells responded poorly to activation signals via the CD3 membrane antigen in both accessory cell-dependent as well as accessory cell-independent culture systems. A similar low response was observed in an anti-CD2-driven system. In contrast, proliferation induced by anti-CD3, anti-CD2, or the phorbol ester Phorbol myristate acetate could be normally enhanced by anti-CD28 MAb. We demonstrated that this unresponsiveness is not due to a failure to induce early events required for activation, such as increased intracellular concentration of free calcium and activation of protein kinase C, but is caused by an imbalance between naive and memory T cells. In HIV-infected asymptomatic men, CD29+ memory T cells are selectively depleted which results in a poor responsiveness to self + X. These findings provide new insights that may have implications for our understanding of the immunopathogenesis of AIDS.

Antibodies, Monoclonal↗
PubMed1989

Whole-blood lymphocyte cultures.

A simple and reproducible method is described for the measurement of proliferative responses of peripheral blood lymphocytes in whole blood upon stimulation with horse anti-human lymphocyte serum (ALS), phytohaemagglutinin (PHA) or a monoclonal antibody (mAb) directed against CD3. Only small aliquots of blood are needed and separation procedures are not necessary. Since the method proved to be very reproducible and showed little variation, reference values of proliferation, expressed in cpm per 15 microliters blood and cpm per 10(3) CD3+ lymphocytes, were determined based upon the 5th and the 2.5th percentile of the distribution of the values in our reference population. In addition, the use of whole blood lymphocyte cultures in longitudinal studies of immunocompromised individuals is demonstrated.

Adolescent↗