Helen M. Hallgren

Acute Lymphoblastic Leukemic Cells with T (Thymus-Derived) Lymphocyte Markers

Five of nine children with acute lymphoblastic leukemia had lymphoblasts that bound sheep erythrocytes or reacted with antiserum to thymocytes, suggesting involvement of T (thymus-derived) cells. When lymphoblasts from all patients were examined by immunofluorescence they were found to lack a marker for B (bone marrow or bursa-equivalent) cells, that is, the presence of surface immunoglobulins.

Lymphocyte subsets and integrated immune function in aging humans

Abstract Lymphocyte response to mitogen stimulation declines in aging humans. Depressed responses to phytohemagglutinin, concanavalin A, and PHA (HA-17) are evident when aged groups are compared to a young adult population. Responding capacity in the mixed lymphocyte reaction declines with age, while stimulating ability remains unaltered. The number of circulating thymus-derived (T) lymphocytes increases in the ninth and tenth decades, while lymphocyte-bearing complement receptors increase in frequency during the fifth through the eighth decades. These observations suggest that T-cell function cannot be equated solely with numbers of circulating immunocompetent cells in aging humans. We have introducted a method of multiple function analysis (pattern recognition) to classify individuals of different ages into groups according to the net-correlated immune functions. The immune functions of an aged population cluster separately from those of a young population.

Lymphocyte proliferative response to PHA and anti-CD3/Ti monoclonal antibodies T cell surface marker expression, and serum IL-2 receptor levels as biomarkers of age and health

Alteration of T cell surface marker expression with a decrease of CD3 positive cells relative to the number of CD4 and CD8 positive cells, diminished in vitro proliferative response to mitogenic stimuli like PHA and antibodies to the CD3/Ti complex, and increase in serum IL-2 receptor levels, are among the changes in immunologic parameters that have been associated with advanced age. To distinguish between effects of the primary aging process and diseases of aging not known to be directly related to immune function, we investigated these variables in two well characterized populations of elderly donors (greater than 70 years) and a young adult control group (less than 35 years). The first group of older donors reported no evidence of significant chronic or recent acute illness and saw a physician only for routine medical care. The second group was randomly selected from individuals seen in a geriatric medicine clinic for diagnoses that included osteoarthritis and cardiopulmonary disorders. Altered surface marker expression and increased serum IL-2 receptor levels were seen only in the second group. On the other hand, lymphocyte proliferative responses to PHA, Leu 4 (anti-CD3) and a monoclonal antibody to the beta-chain of the T cell antigen receptor (WT31) were significantly decreased in both populations. Because we would expect primary aging to affect even extremely fit individuals of advanced age, we conclude that decrease in T cell proliferative response may represent a biomarker of primary aging in man. The alteration in surface marker expression and increased IL-2R levels in serum appear to be effects secondary to non-immunologic disease rather than aging.

The effect of DHEAS on influenza vaccination in aging adults.

OBJECTIVE: To determine whether simultaneous administration of dehydroepiandrosterone sulfate (DHEAS) exhibits adjuvant activity in the immune response of aging humans by supplementing influenza vaccination with the maximum single dose of DHEAS that could be practically injected subcutaneously (approximately 7.5 mg).

Evidence for origin of certain childhood acute lymphoblastic leukemias and lymphomas in thymus‐derived lymphocytes

Lymphoblasts from children with acute lymphoblastic leukemia (ALL) or malignant lymphoblastic lymphoma were studied using surface markers characteristic of T and B lymphocytes. A B‐cell marker, i.e. surface immunoglobulin, was absent in all cases studied. Fourteen of 22 children (64%) had lymphoblasts with one or both markers of T lymphocytes, i.e. receptors for sheep erythrocytes (E) and/or human T‐lymphocyte antigen (HTLA) detectable using heterologous antithymocyte sera absorbed with B lymphocytes. In all instances, lymphoblasts which carried E receptors also carried HTLA. However, lymphoblasts in 6 cases carried HTLA but not E receptors. It is possible that ALL may often involve T lymphocytes which are early in differentiation (i.e. prior to development of E receptors) or, alternatively, that E receptors may be lost from T cells following malignant transformation. Thymus enlargement was found only in cases of ALL or lymphoma where T markers were present. Lymphoblasts carried the same markers when examined in various sites and at various times from the same patient.

Do immature T cells accumulate in advanced age

The hypothesis that decreased T cell function in the elderly involves an increased number of less differentiated T cells was examined. Three markers known to change during thymocyte development were analyzed; ratio of adenosine deaminase (ADA) to purine nucleoside phosphorylase (PNP), lactate dehydrogenase (LD) H/M subunit ratios and the T cell associated antigens, T3, T4, T8 and T10. Cells tested were from 10 old (greater than 75 years) and 10 young (less than 35 years) persons with equal numbers of males and females in each group. Before analysis, cells were purified into three groups; unfractionated, and monocyte depleted T cell and B cell enriched populations. Results for ADA/PNP ratios showed no significant differences between old and young in any of the fractions analyzed. H/M ratios however, were significantly reduced in all three fractions from old donors when compared with young. Surface marker distribution pattern as illustrated by the T3 - (T4 + T8) difference was lower in samples from old donors but not significantly so. There was a very significant reduction in percent cells positive for T3 in all three fractions from old persons. Although some of the changes seen in these markers could be due to a failure of normal differentiation, they could also be caused by the general phenomenon of altered gene expression known to occur with advanced age in a variety of non-lymphoid cells. The absence of any difference in the ADA/PNP ratio suggests that T cell dysfunction in the elderly may not be due to increased numbers of less differentiated cells as a result of thymic involution.

Effects of preliminary culture on the membrane microviscosity of lymphocytes from young and old donors. Microviscosity correlates with mitogenic response

Membrane microviscosity was assessed by a fluorescence polarization technique in fresh and precultured human peripheral blood lymphocytes of young and old subjects. Membrane microviscosity was significantly higher in fresh, non-treated cells of old donors as compared to young adults. Preincubation of cells in culture medium supplemented with pooled human serum diminishes the original microviscosity difference between the age groups. The observed increase in membrane fluidity correlates with the improvement of the mitogen-induced proliferative response due to preculturing cells from aged subjects. The results support the suggestion that membrane microviscosity can affect the proliferative response of lymphocytes, and it may play a role in the decline of the immune responsiveness in the elderly.

Evidence for expansion of a population of lymphocytes with reduced or absent T3 expression in aged human donors

In a previous report, we described an unusual pattern of T cell associated surface marker expression in unfractionated mononuclear cells from aged donors; an excess of T4 and T8 positive cells relative to T3 positive cells. This study further characterizes these cells on the basis of density, adherence to nylon wool and quantitative expression of cell surface markers. We find that the population of lymphocytes responsible for the unusual surface marker expression is of low density, adheres to nylon wool, and is present in small numbers in young donors. The adherent cells have a reduced quantitative expression of the T3 antigen, no change in the antigen density of T4 and T8, and have increased expression of the T10 antigen. These cells do not have the characteristics of large granular lymphocytes, monocytes, B cells with unusual marker expression, or thymocytes poised for export to peripheral blood. We suggest that these cells, found in increased numbers in aged humans, may represent an expansion of a population of T lymphocytes with absent or reduced T3 antigen expression found normally in smaller numbers in young adults. T lymphocyte antigen receptor density has been quantitatively linked to expression of the T3 antigen. Thus, our results imply that aging may lead to decreased T cell surface antigen density, which may account in part for decline in T cell function with age.

Histocompatibility determinants in idiopathic scoliosis.

The HLA antigen distribution in 64 random scoliosis patients has been determined. Of the surgical group (greater than 50 degrees), the specificity W19 was increased. In the nonsurgical group (less than 45 degrees) the W19 specificity was also increased; however, the only specificity significantly increased was A29 (X2=11.64, P=less than .02). These observations are preliminary and more extensive work is needed to establish the relevance of the major histocompatibility system in the etiology and progression of idiopathic scoliosis.