Fred Rosen

IMPLANTATION OF A FŒTAL THYMUS, RESTORING IMMUNOLOGICAL COMPETENCE IN A PATIENT WITH THYMIC APLASIA (DiGEORGE'S SYNDROME)

Abstract A 21-month-old male with congenital aplasia of the thymus (DiGeorges syndrome) underwent implantation of thymus fragments from a 16-week-old female foetus. Abnormalities of lymphocyte function as manifested by failure to reject a skin allograft, to develop delayed hypersensitivity to Monilia and dinitrofluorobenzene, or to respond to phytohaemag-glutinin were promptly rectified. There was no evidence of a graft-versus-host reaction.

Identification and characterization of subpopulations of lymphocytes in human peripheral blood after fractionation on discontinuous gradients of albumin. The cellular defect in X-linked agammaglobulinemia.

Normal human peripheral blood lymphocytes were separated on discontinuous gradients of 17-35% bovine serum albumin (BSA) into nine fractions. Three subpopulations of lymphocytes were obtained. One occupies the top third of the gradient (fractions 1-3, 17-23% BSA) and is rich in cells characterized by a high spontaneous rate of DNA synthesis and by the ability to give rise to colony-forming units. The middle portion of the gradient (fractions 4 and 5, 23-27% BSA) is rich in thymus-derived (T) lymphocytes identified by their vigorous response to mitogens and by their ability to form rosettes with sheep erythrocytes (E). The third subpopulation at the bottom of the gradient (fractions 6-9, 27-35% BSA) is rich in bone marrow-derived (B) lymphocytes capable of staining with fluorescent antiimmunoglobulin antisera and of forming rosettes with EAC1423. The peripheral blood lymphocytes of five boys with proved X-linked agammaglobulinemia and two with probable X-linked agammaglobulinemia were found to be totally deficient in B lymphocytes (fractions 6-9) and lacked the subpopulation identified by immunofluorescent staining or rosette formation with EAC1423. One boy with proved X-linked agammaglobulinemia and two with probable X-linked agammaglobulinemia possessed a normal amount of circulating B lymphocytes.

Primary immunodeficiency diseases: an update

Although relatively rare, primary immune deficiency diseases (PIDs) provide an excellent window into the functioning of the immune system. In the late 1960s, observations on these diseases, with their associated infections and genetics, bisected the immune system into humoral immunity and cell-mediated immunity. These diseases also represent a challenge in their diagnosis and treatment. Beginning in 1970, a unified nomenclature for the then-known primary immunodeficiency diseases was created by a committee convened by the World Health Organization. Since then, and later under the aegis of the International Union of Immunological Societies, an international committee of experts has met every 2 to 3 years to update the classification of PIDs. During the past 15 years, the molecular basis of more than 100 PIDs has been elucidated. This update results from the latest meeting of this committee in Sintra, Portugal, June 2003, which followed 2(1/2) days of scientific discussions.

C1 Inhibitor: Evidence for Decreased Hepatic Synthesis in Hereditary Angioneurotic Edema

Although the Cl inhibitor was detected in 5 to 10 percent of normal hepatic parenchymal cells by means of the immunofluorescent technique, none was seen in liver biopsies from two individuals with hereditary angioneurotic edema having low concentrations of Cl inhibitor in the serum. In contrast, the percentages of cells which reacted with fluorescent antiserums to C4 and transferrin were normal. These data suggest that in most subjects with hereditary angioneurotic edema, there is decreased synthesis of the C1 inhibitor but normal synthesis of C4, and that the disease results from this biosynthetic error.

Purine nucleoside metabolism in the erythrocytes of patients with adenosine deaminase deficiency and severe combined immunodeficiency.

Deficiency of erythrocytic and lymphocytic adenosine deaminase (ADA) occurs in some patients with severe combined immunodeficiency disease (SCID). SCID with ADA deficiency is inherited as an autosomal recessive trait. ADA is markedly reduced or undetectable in affected patients (homozygotes), and approximately one-half normal levels are found in individuals heterozygous for ADA deficiency. The metabolism of purine nucleosides was studied in erythrocytes from normal individuals, four ADA-deficiency patients, and two heterozygous individuals. ADA deficiency in intake erythrocytes was confirmed by a very sensitive ammonia-liberation technique. Erythrocytic ADA activity in three heterozygous individuals (0.07,0.08, and 0.14 mumolar units/ml of packed cells) was between that of the four normal controls (0.20-0.37 mumol/ml) and the ADA-deficient patients (no activity). In vitro, adenosine was incorporated principally into IMP in the heterozygous and normal individuals but into the adenosine nucleotides in the ADa-deficient patients. Coformycin (3-beta-D-ribofuranosyl-6,7,8-trihydroimidazo[4,5-4] [1,3] diazepin-8 (R)-ol), a potent inhibitor of ADA, made possible incorporation of adenosine nucleotides in the ADA-deficient patients...

Corticosteroids and Enzyme Activity

Publisher Summary This chapter describes those enzymes that are altered following adrenalectomy or the administration of corticosteroids. The current literature on this subject is descriptive rather than interpretive. Although it bridges the interest of endocrinologists, pharmacologists, and biochemists, few answers are to be found at present to the questions most relevant to each of these fields. In developing some perspective concerning reports of metabolic changes that underlie corticosteroid effects, it is well to recognize the preponderance of reports concerning enzymes in liver. The less-studied changes in peripheral tissues responsive to the presence of corticosteroids are of equal, if not greater, significance in understanding the primary effects of these agents. Too few simultaneous studies of metabolic changes in liver and lymphoid tissues have been carried out. Also, in most enzymatic studies, rodent tissues have been examined as a matter of convenience. Evidence for comparable changes in human tissues would be very important, yet little or no such information is available. Information cannot be extrapolated from rodents or other species to the human in the absence of substantial comparative data.

ESTABLISHMENT OF IMMUNOLOGICAL COMPETENCE IN A CHILD WITH CONGENITAL THYMIC APLASIA BY A GRAFT OF FETAL THYMUS

Abstract Fetal thymus tissue was implanted into a 21-month-old patient with congenital aplasia of the thymus gland (DiGeorges syndrome). Clinical and immunological studies carried out for 16 months thereafter revealed prompt and long-lasting improvement in previously defective cellular immune functions including dermal sensitivity to monilia antigen and dinitrofluorobenzene, skin allograft rejection, and the responses of peripheral blood leucocytes in vitro to phytohaemagglutenin and to monilia antigen. It is suggested that implanting fetal thymus tissues into patients with DiGeorges syndrome offers at present the best hope of improving their deficient cellular immune function.

Acquired deficiency of the inhibitor of the first component of complement: Report of five additional cases with commentary on the syndrome

The association of late onset recurrent angioedema with a deficiency of the inhibitor of the first component of complement (C1INH) and of the binding subunit of the first component, Clq, defines the syndrome of acquired C1INH deficiency. The description of five new cases, along with the original two and the 18 others in the literature, brings the total reported cases to 25 and highlights the associated B cell abnormalities that are present in 23 and are of a malignant nature in 19 cases. In three of the five newly reported cases, the occurrence of angioedema, which prompted recognition of the acquired deficiency of C1INH, C1q, and C4, preceded the delineation of the underlying B cell malignancy by 2 to 3 yr despite efforts to recognize neoplastic disease in two of these patients throughout the interval. Because the acquired C1INH deficiency reflects increased catabolism rather than impaired biosynthesis, only high-dose attenuated androgens elicit a measurable increment in serum C1INH. The occurrence of the syndrome with multiple myeloma is noted for the first time.

Cortexolone: Binding to glucocorticoid receptors in rat thymocytes and mechanism of its antiglucocorticoid action

Abstract In rat thymocytes, cortexolone (11-deoxycortisol) competes for binding to glucocorticoid receptors, as identified on sucrose density gradients, and blocks the effect of triamcinolone acetonide (TA) on 2-deoxyglucose uptake. The cellular distribution and sedimentation coefficients of 3H-TA-receptor complexes are dependent on the incubation temperature and ionic strength of the extraction buffer. In contrast, the single receptor complex formed by 3H-cortexolone has a sedimentation coefficient of 3.5S, and is unaffected by changes in temperature and salt concentration.

Glucocorticoid activity of various progesterone analogs: correlation between specific binding in thymus and liver and biologic activity.

When tested in an in vitro assay system, progesterone and various analogs of this steroid were shown to compete with [3H] triamcinolone acetonide (TA) for specific glucocorticoid receptors in both rat liver and thymus. Of these analogs, the following derivatives of progesterone were potent competitors of TA binding and, when injected into adrenalectomized rats, induced regression of the thymus and marked increases in hepatic tyrosine aminotransferase activity: 11 beta-hydroxyl, 6 alpha-methyl, 6 alpha, 16 alpha-dimethyl, and 6 alpha-methyl-17 alpha-hydroxyl. In contrast, progesterone, 16 alpha-methyl, and 17 alpha-hydroxy progesterone competed with TA in vitro but failed to elicit either gluco- or antiglucocorticoid activity in vivo. Also, we observed that the oral contraceptive 6 alpha-methyl-17-(1-propynyl)testosterone competes very effectively with TA in a cell-free preparation of rat liver and induces an increase in hepatic tyrosine aminotransferase activity. The 11 beta-hydroxyl group has previously been thought to be essential for glucocorticoid activity. Our studies indicate that substitution of progesterone or testosterone with a 6 alpha-methyl group negates the need for an 11 beta-hydroxyl substitutuent as a prerequisite for glucocorticoid activity.