Ten years after acquiring an HIV-1 infection: a study in a cohort of eleven neonates infected by aliquots from a single plasma donation.

We present data from a 10-year follow-up study of 11 children who had been infected in the neonatal period by small aliquots of plasma from a single donation. Three of the children died within the first 2.5 years of life, 5 other children died between 6.2 and 11 years after infection and 3 are alive at present. The latter children are classified as P1B (asymptomatic), P2A (non-specific findings) and P2B (neurological changes). All infected children showed progressive decline of cellular immunity. Immunoglobulin levels in serum were increased in the majority of children for prolonged periods and homogeneous immunoglobulin components were present. The severity of the disease was related neither to the clinical condition of the infants in the neonatal period nor to the volume of transfused plasma, the interval between freezing and thawing of the plasma, gestational age at birth and age at transfusion. Coinciding infections with other viruses had no impact on disease progression during the follow-up period of 10 years.

Failure of calcitriol treatment in a patient with malignant osteopetrosis.

In an attempt to stimulate bone resorption, a 10-week-old infant with malignant infantile osteopetrosis was treated with high doses of calcitriol, a potent bone resorption stimulatory agent, combined with a low calcium diet to prevent hypercalcaemia. Although calcitriol administration was initiated at this very young age, our patient did not show any clinical, radiological, or histological improvement. Despite reports of positive results of this treatment in the literature, our patient did not reveal any signs of bone resorption. She eventually died from the complications of osteopetrosis at the age of 6 months after 88 days of therapy.

[The clinical significance of anti-gliadin antibodies determination in blood of children with suspected celiac diseases]. / De klinische waarde van de bepaling van anti-gliadine antilichamen in het serum van kinderen met verdenking van coeliakie.

Screening tests for coeliac disease may be useful to select the patients who should undergo a small intestine biopsy. It has been reported that the determination of serum levels of anti-gliadin antibodies is a good screening method for small intestine damage in coeliac disease. We have retrospectively assessed the value of the anti-gliadin antibody test in detecting villous atrophy of the small bowel. Antigliadin antibodies were measured with an ELISA technique in sera of 44 children seen at the Department of Paediatrics, Leiden University Hospital, who underwent 53 small intestine biopsies because of suspected coeliac disease. The relation between the histopathological findings of the small intestine and the results of the anti-gliadin antibody quantifications in serum were studied. In 9 of the 10 children with villous atrophy high Ig total and IgG-titers were found. Five children with villous atrophy, 2 of them with a selective IgA-deficiency, had normal IgA-AGA titers in serum. 17 Children with normal biopsies had high Ig total and IgG-AGA titers, but no child with normal small intestine biopsy had high IgA-AGA titers in serum. We conclude that the determination of anti-gliadin antibodies as screening for mucosal damage must be based on the measurement of antibodies within the IgG as well as the IgA class.

Expression of HLA-DQ antigens in the small-intestinal mucosa of patients with coeliac disease.

Studies at the DNA and product level of B-cell lines of coeliac patients have shown a strong association between coeliac disease and the HLA-DQ alpha 2.3 and HLA-DQ beta 2.7 alleles. The monoclonal antisera SFR20-DQ alpha 5 and XIII-358.4, which specifically react with HLA-DQ alpha 2.3 and with HLA-DQ beta 2.3 and -DQ beta 2.7, respectively, have been used to detect the expression of these specificities in the small-intestinal mucosa of 7 coeliac patients and 11 non-coeliac persons. An immunoperoxidase technique on frozen tissue sections of jejunal biopsy specimens was used. Positive specimens showed immunoperoxidase staining of lymphocytes and histiocytes in the lamina propria. The epithelial cells showed no immunoperoxidase staining. Positive results at the intestinal level correlated with the HLA typing of the patients and controls. The distribution found for the HLA-DQ alleles in the intestinal mucosa makes the role of a HLA-DQ alpha/beta dimer as gliadin receptor at the epithelial cell less probable, but it is compatible with the hypothesis that these DQ molecules are involved in the regulation of the intestinal immune response to gluten.

Prevention of infection and graft-versus-host disease by suppression of intestinal microflora in children treated with allogeneic bone marrow transplantation.

The effect of suppression with antimicrobial agents of the intestinal microflora of paediatric bone marrow graft recipients on severe bacterial and fungal infections and on moderate to severe acute graft-versus-host disease was studied retrospectively. Data on 65 cases of bone marrow transplantation for either severe bone marrow failure or leukaemia, performed in a strict protective environment with either complete or selective gastrointestinal decontamination, were evaluated. All bone marrow grafts were from HLA-identical siblings and were not depleted of T-lymphocytes. Twenty percent of the recipients had one or more episodes of septicaemia during the granulocytopenic period after transplantation, mostly due to gram-positive bacteria. Only five children died due to infection, in each case caused by a microorganism originating from the endogenous flora. Complete gastrointestinal decontamination was superior to selective gastrointestinal decontamination in preventing infectious complications (p less than 0.001). The same was the case for the prevention of acute graft-versus-host disease of grade II or higher, which was observed in 7 of 40 (17.5%) completely decontaminated children versus 9 of 18 (50%) selectively decontaminated children evaluable for graft-versus-host disease (p less than 0.01). It is concluded that complete gastrointestinal decontamination in a strict protective environment is a feasible and very effective method for preventing severe infections and acute graft-versus-host disease after allogeneic bone marrow transplantation in children and adolescents; it resulted in a low transplantation-related mortality of 26% and a good quality of survival in 69% of the graft recipients.

[Combined immunologic deficiency]. / Gecombineerde immunologische deficiëntie.

In the last 20 years 32 patients with severe combined immunodeficiency (SCID) were treated at our department. The clinical and immunological findings in these patients are presented. In connection with these patients, the recent WHO classification on combined immunodeficiency diseases and the pathogenesis in several forms of SCID, as far as is known, are discussed. SCID appears to represent a very heterogeneous group of disorders, which is affirmed by the findings in several of our patients. At this moment bone marrow transplantation (BMT) is the only way to cure patients with SCID. Without this treatment the prognosis of these patients is very poor. After BMT complete recovery is achieved for the majority of patients, even in the absence of a genotypically HLA identical donor. Besides the therapeutic aspects of SCID the recent developments with regard to carrier-detection and antenatal diagnosis are briefly discussed.

[AIDS in children]. / AIDS bij kinderen.

Infection with the human immunodeficiency virus type I in children causes variable clinical symptoms. It can lead to asymptomatic disease as well as to acquired immunodeficiency syndrome. In this review we describe the clinical picture, the immunological abnormalities, the mode of transmission, and the preventive measures in case of HIV-I infection.

Correction of lysosomal enzyme deficiency in various organs of beta-glucuronidase-deficient mice by allogeneic bone marrow transplantation.

The correction of lysosomal enzyme deficiency was investigated for various organs of beta-glucuronidase-deficient C3H/Rij mice after allogeneic bone marrow transplantation from an enzymatically normal donor strain (C57BL/Rij). In the hemopoietic organs, the enzyme level increased to levels found in donor mice. In lung, kidney, liver, and peripheral nervous tissue, a significant increase in enzyme activity was seen to levels intermediate between those of donor and recipient. Increased enzyme activity was maintained throughout the observation period of 150 days. In skeletal muscle tissue, enzyme levels tended to be higher in recipient mice, but this increase was not significant for all data points. Bone marrow transplantation failed to significantly affect enzyme activity in central nervous system tissue. These data suggest that beneficial effects expected from bone marrow transplantation for lysosomal enzyme deficiencies depend on the type of tissue involved in the disease. In diseases severely affecting the central nervous system, cure may not be expected from bone marrow transplantation alone, whereas in diseases with only minimal central nervous system involvement, alleviation or prevention of clinical symptoms may occur.

Natural killer (NK)-cell activity in sorted subsets of peripheral blood mononuclear cells from patients with severe combined immunodeficiency.

Natural killer-cell activity for K562 target cells was measured in 13 patients with severe combined immunodeficiency before bone marrow transplantation. Both unseparated peripheral blood mononuclear cells and sorted cell subsets (B73.1 positive, B73.1 negative, OKT3 positive, OKT3 negative) were tested. Heterogeneity of natural killer-cell activity was observed, the level of which did not correlate with the usual subdivision of severe combined immunodeficiency, as defined by a scientific group on immunodeficiency for the WHO. In those patients in whom natural killer-cell activity was observed in unseparated cells, testing of this function in sorted cell subsets revealed some unexpected findings. In three of four patients, B73.1-negative cells showed remarkable natural killer-cell activity. In addition, in one of these patients, no activity was observed in the B73.1-positive cells.

Transient elevation of serum IgE after allogeneic bone-marrow transplantation.

Serum IgE levels were followed longitudinally twice a week for up to 100 days in 60 children treated for leukemia, severe aplastic anemia or severe combined immunodeficiency: 52 underwent allogeneic bone-marrow transplantation and 8 immunosuppressive treatment. In 55 of 58 treatment periods which could be analyzed (95%), a transient sharp increase of serum IgE was detected, irrespective of the initial diagnosis and mode of treatment. A second IgE peak was recorded in 16% of evaluable treatment periods. In the transplanted leukemia and aplastic anemia patients, the rise of serum IgE levels occurred at the same time, i.e. at a mean of 14 days after transplantation; it occurred significantly later in children grafted for severe combined immunodeficiency. In children who received immunosuppression for the treatment of severe aplastic anemia, IgE elevations were always seen within 2 weeks after institution of therapy. No relation was found between either the occurrence of clinically acute graft-versus-host disease or infections after treatment, and the time of onset of IgE elevations. It is suggested that the phenomenon of IgE peaks in the population of patients investigated was due to disturbance of T-cell regulation, i.e. a temporary impairment of T-suppressor cell activity.

Bone marrow transplantation in man. Analysis of T and B cell functions in PWM driven Ig production.

The functional activity of B and T lymphocytes from the blood of eight patients, who had successfully been treated with allogeneic bone marrow for severe aplastic anaemia or acute leukaemia, was studied in pokeweed mitogen (PWM) driven polyclonal immunoglobulin synthesis. Activity of B cells was measured as IgM and IgG synthesis by a standard number (40 X 10(3] of patient lymphocytes in the presence or absence of healthy donor T cells. In addition, the frequency of PWM reactive B cells, giving rise to IgM and/or IgG producing daughter cells, was estimated by limiting dilution analysis. With this method, it was found that only a small percentage (1-3%) of peripheral blood B cells from healthy individuals is reactive to PWM. In the patients, both parameters for B cell reactivity were decreased during the first 40 weeks after bone marrow transplantation. As parameters for T cell activity, help and suppression on the Ig production by healthy donor lymphocytes were tested. In most patients, T helper cell activity was strongly decreased, whereas some patients had excessive T suppressor cell activity. The observed functional activities were only partially correlated with the marker profile of the T cell populations, as detected by reactivity with monoclonal antibodies. Each patient had a distinct, individual pattern of reconstitution of these functions. There was no positive correlation between Ig production in vitro and the capacity to form antibodies in vivo, nor between the other in vitro findings and clinical features, such as the occurrence of infections or graft versus host disease.

Bone marrow transplantation in children with severe aplastic anemia: reconstitution of cellular immunity.

Cellular immune functions were evaluated longitudinally in seven children with severe aplastic anemia, who were successfully transplanted with bone marrow cells from an HLA-identical, mixed lymphocyte culture (MLC)-negative sibling. Several parameters were followed: the number of lymphocytes and E rosette-forming cells in the peripheral blood and the lymphocyte reactivity toward various mitogens, antigens, and allogeneic lymphocytes. Some patients already displayed decreased in vitro lymphocyte reactivity before transplantation, especially with regard to the response to pokeweed mitogen (PWM). After transplantation, a severe cellular immunodeficiency developed in all patients, with low numbers of T cells and markedly impaired responsiveness to mitogens, antigens, and allogeneic lymphocytes. Variations between patients were substantial, both with regard to the severity and duration of the immunodeficiency and to the pattern of the recovery of lymphocyte responses to mitogens and antigens. This variability might be attributable to an imbalanced proliferation of different lymphocyte subsets and/or the sequence of appearance of receptors for mitogens on the cell surface.

T lymphocyte characteristics in bone marrow-transplanted patients. II. Analysis with monoclonal antibodies.

The relative distribution of T cell subsets, as defined by the monoclonal antibodies OKT, was analyzed in peripheral blood lymphocytes of 8 children after bone marrow transplantation for aplastic anemia. The percentage of peripheral blood lymphocytes binding OKT3 (directed against a common T cell surface antigen and defining most peripheral T cells) reached normal values shortly after transplantation. In 5 patients, lymphocytes binding OKT8 (directed against an antigen present on the suppressor/cytotoxic T cell subset) were found in high proportion, and lymphocytes binding OKT4 (detecting an antigen present on inducer/helper T cells) in low percentage. This resulted in an inverted ratio OKT4/OKT8 compared with that of lymphocytes from normal individuals. In all patients the lymphocytes bound abnormally high amounts of OKT10 (directed against an antigen present on all thymocytes but not on mature peripheral T cells). In the course of time, a trend towards normalization was observed for all parameters investigated; however, the kinetics of the recovery showed a marked heterogeneity. From the analysis of this phenomenon, it is likely that, among other conditions yet unknown, a minimum of 20% of OKT4-positive lymphocytes is required for a normal proliferative response to T cell mitogens in vitro. No other correlation was found between any lymphocyte phenotype, as defined by the OKT antibodies, and proliferative response in vitro. Furthermore, lymphocytes from the patient with chronic graft-vs-host disease (greater than 50% OKT8 positive) failed to suppress the proliferative response to mitogens and antigens of the lymphocytes of the histo-identical bone marrow donor.