Hilaire J. Meuwissen

Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy

We have reported a male infant whose mother was treated throughout pregnancy with large doses of azathioprine and prednisone for chronic renal disease. At birth, the child manifested lymphopenia, diminished thymic radiographic shadow, and low serum concentrations of immunoglobulins M and G. Cytomegalovirus (CMV) was cultured from maternal urine and from the infants urine at 10 weeks of age. The patient developed satisfactorily in the postnatal period and his immune status returned to normal. More than one year after birth the child appears to have developed adequately and, with the exception of low serum IgA concentration and persistent CMV infection, appears to have intact immunologic responses. Our observations in this patient and information derived from a literature review emphasize the need for short-and long-term clinical and laboratory evaluation of infants born to mothers who have been receiving immunosuppressive and potentially carcinogenic drugs during pregnancy.

Bronchus-associated lymphoid tissue in human lung: Correlation of hyperplasia with chronic pulmonary disease

Abstract Nine patients with chronic or recurrent pneumonia had as a principal abnormality the presence of lymphoid masses around the bronchi and bronchioles. Many small airways were obstructed or destroyed. We found that the lymphoid tissues had characteristics of bronchus-associated lymphoid tissue (BALT). While BALT performs an essential immunologic function in airways, hyperplasia of this structure may contribute to bronchial pathology.

Normal Fibronectin Levels as a Function of Age in the Pediatric Population

Summary: Fibronectin is an important non-immune opsonic protein influencing phagocytic clearance of blood-borne nonbacterial particulates which may arise in association with septic shock, tissue injury, and intravascular coagulation. In the present study, serum fibronectin was measured by both electroimmunoassay as well as rapid immunoturbidimetric assay in healthy children (n = 114) ranging in age from 1 month to 15 years in order to delineate the temporal alterations in fibronectin with age. Normal adult serum fibronectin concentrations are typically 220 μg/ml ± 20 μg/ml. Serum concentration is 35–40% lower than normal plasma concentration due to the binding of fibronectin to fibrin during clot formation. Children between 1–12 months of age bad significantly (P < 0.05) lower serum fibronectin levels than children between the ages of 1–15 years. Progressive elevation in fibronectin levels was observed within the last 8 months of the first year of age. Fibronectin levels in children older than 1 year of age remained constant up to 15 years and were within the lower limit of the normal adult concentration. No significant (P > 0.05) difference in serum fibronectin was observed between male and female children at all age groups. Fibronectin levels thus, increase during the first year of age and normal levels of this blood protein in the infant are less than the normal range for adults.

Screening for ADA deficiency

A screening test for ADA deficiency is described which can be performed on blood spotted on filter paper. Thetest depends on pH reagents incorporated into a gel containing adenosine, which change color as ammonia is released in the presence of ADA. The method is about 97% accurate and is simple and inexpensive to perform. Such screening may be useful in the early detection of the type of combined immune deficiency associated with markedly reduced activity of this enzyme.

Long-term survival after bone marrow transplantation: A 15-year follow-up report of a patient with wiskott-aldrich syndrome

In 1968 a 2-year-old boy with Wiskott-Aldrich syndrome was extremely ill with eczema, a series of life-threatening infections, and repeated hemorrhages into his skin, lungs, brain, and other internal organs. He was given high-dose cyclophosphamide therapy for immunosuppression, followed by bone marrow cells from his histocompatible, healthy sister. In the 15 years since bone marrow transplantation, he has had full T cell, partial B cell, and no hematopoietic engraftment. He has weathered the usual infectious diseases of childhood, has had no serious infections, and despite persistent thrombocytopenia has not had serious bleeding episodes.

717 MARROW TRANSPLANTATION (MTP) IN WISKOTT-ALDRICH SYNDROME (WAS): T CELL ENGRAFTMENT WITH CYCLOPHOSPHAMIDE (CY), COMPLETE ENGRAFTMENT WITH TOTAL BODY IRRADIATION

We studied two patients with WAS who had MTP with marrow from HLA-identical siblings. The first patient received 200 mg/kg CY over 4 days (Bach et al., Lancet 1:1364, 1968). We have followed this patient for 7 years. He has petechiae, bleeding in joints, and severe thrombocytopenia. IgM has remained low; antibody production to some antigens, lymphocyte response to mitogens and in vitro B cell functions are defective. Growth and development have been normal. The second patient received cytosine arabinoside 5 mg/kg/day ×7, 6-thioquanine 4 mg/kg/day ×7, and CY 50 mg/kg/day ×4 prior to MTP. In both patients after MTP, megakaryocytes, red cells, neutrophils, macrophages, and most B cells remained of recipient type while most T cells were of donor type. The second patient was retransplanted after preparation with anti-lymphocyte globulin, 2 ml IV daily x4, Procarbazine, 12.5 mg/kg/day × 3, and 800 R total body irradiation. Ninety days after the 2nd transplant, all nucleated marrow and blood cells, including B and T cells were of donor type; WBC 12,500, platelets 132,000/mm3, hemoglobin 9.8 gms % and reticulocytes 3.5%. No graft-versus-host disease was observed. We conclude that in marrow transplantation for WAS, 200 mg/kg CY may be inadequate preparation. In WAS, T cells may more readily be engrafted than other blood cells. Supported by USPHS GCRC #MO-1-R00749-05.

Successful retransplantation of bone marrow following failure of initial engraftment in a patient with aplastic anemia

Histobompatible sibling bone marrow was transplanted to a patient withsevere aplastic anemia. The first transplant failed, but a second transplantfrom the same donor was successfully performed with a new and more potentimmunosuppressive regimen. Successful retransplantation after marrow graftrejection is now possible.

TISSUE ADENOSINE DEAMINASE ACTIVITY IN AN ADENOSINE DEFICIENT-COMBINED IMMUNODEFICIENCY DISEASE PATIENT

Patients with combined immunodeficiency (CID) and adenosine deaminase (ADA) deficiency may have low or absent ADA activity in various tissues. Hirschhorn et al. have shown that the activity in patient fibroblasts is a mutant form of ADA (PNAS 73: 213, 1976). Others have suggested that the deficiency reflects an inhibition of ADA (Trotta et al., PNAS 73: 104, 1976). We have isolated and in part characterized properties of the residual ADA from spleen of one patient. Radioimmunoassay for ADA protein in erythrocytes and spleen extracts of the patient showed no cross-reacting protein. Chromatography of ADA-CID spleen extracts produced a fraction with adenosine deaminating activity which could not be adsorbed on affinity or anti-ADA columns. The deaminating activity could not be inhibited with erythro-9-(2-hydroxyl-3-nonyl) adenosine. The pH optimum activity curve and Km differed from normal spleen ADA. A similar fraction, representing about 1% of the total ADA activity, was isolated from normal spleen extracts. We conclude that the adenosine deaminating activity observed in patients with ADA-CID is not ADA. The activity may be due to an enzyme whose principal substrate may be another metabolite. The presence of this non-ADA deaminating activity in normal spleen suggests that the observed activity in ADA-CID tissue is not due to a mutant form of ADA and that the inhibited enzyme activity reported by Trotta et al. may be due to an amplification of this non-ADA deaminating enzyme.

SUCCESSFUL MARROW RE-TRANSPLANTATION FOLLOWING FAILURE OF FIRST TRANSPLANT FOR APLASTIC ANEMIA

An 11 year old girl with aplastic anemia of unknown etiology was transplanted with MLC and HLA identical sibling marrow following 4 doses of Cyclophosphamide (CY) 50 mg/kg. She had received multiple blood transfusions before transplantation (TP). Three weeks following TP the marrow was repopulating, but 4 weeks later the marrow was again aplastic. Immunosuppression with Procarbazine, anti-thymocyte globulin, and a repeat course of CY were given followed by a second TP from the same donor. A take of donor marrow cells now occurred and has persisted to the present (140 days after TP). No evidence of graftversus-host disease was seen; PHA responsive peripheral blood lymphocytes have remained predominantly of host type. The patient has remained in excellent clinical health. Her B cell function is normalizing, but her T cell function is as yet depressed.

ADA Deficiency – The First Described Genetic Defect Causing PID

The serendipitous discovery of adenosine deaminase (ADA) deficiency in 1972 preceded by two decades the identification of gene defects in other forms of severe combined immune deficiency (SCID). During that interval, a great deal was accomplished: with knowledge of the underlying enzyme deficiency came a biochemical test for diagnosing ADA-deficient patients. The metabolic consequences of ADA deficiency were determined, the biochemical mechanisms by which ADA substrates and metabolites cause disease were defined and the close relationship of genotype to phenotype became apparent. A novel method of enzyme replacement for ADA deficiency was tested and approved, and the first in human trial of gene therapy was initiated in patients with ADA deficiency.