Adoptively Transferred Dendritic Cells Restore Primary Cell-Mediated Inflammatory Competence to Acutely Malnourished Weanling Mice

Abstract

Immune depression associated with prepubescent malnutrition underlies a staggering burden of infection-related morbidity. This investigation centered on dendritic cells as potentially decisive in this phenomenon. C57BL/6J mice, initially 19 days old, had free access for 14 days to a complete diet or to a lowprotein formulation that induced wasting deficits of protein and energy. Mice were sensitized by i.p. injection of sheep red blood cells on day 9, at which time one-half of the animals in each dietary group received a simultaneous injection of 10 6 syngeneic dendritic cells (JAWS II). All mice were challenged with the immunizing antigen in the right hind footpad on day 13, and the 24-hour delayed hypersensitivity response was assessed as percentage increase in footpad thickness. The low-protein diet reduced the inflammatory immune response, but JAWS cells, which exhibited immature phenotypic and functional characteristics, increased the response of both the malnourished group and the controls. By contrast, i.p. injection of 10 6 syngeneic T cells did not influence the inflammatory immune response of mice subjected to the low-protein protocol. Antigen-presenting cell numbers limited primary inflammatory cellmediated competence in this model of wasting malnutrition, an outcome that challenges the prevailing multifactorial model of malnutrition-associated immune depression. Thus, a new dendritic cell-centered perspective emerges regarding the cellular mechanism underlying immune depression in acute pediatric protein and energy deficit. (Am J Pathol

Malnutrition alters the rates of apoptosis in splenocytes and thymocyte subpopulations of rats

“…Analysis of immunocompetent cells at the activation stage and of subsequent processes of excessive and insufficient apoptosis may be of importance in the knowledge of the immunopathogenesis of many diseases. Better understanding of the molecular and cellular changes made in response to inadequate nutrients should lead to the development of immunotherapeutic interventions [35]. The study of the inter‐relationships between nutritional status and cell death is in its first phase, with much remaining to be learned.…”

Fidelity in Animal Modeling: Prerequisite for a Mechanistic Research Front Relevant to the Inflammatory Incompetence of Acute Pediatric Malnutrition

“…It would be shortsighted to dismiss the potential of the low-protein stunting model as a laboratory tool with which to probe immunological plasticity, but focusing on a detail of dietary composition rather than on details of a pathophysiology has produced a type of animal model bearing no clear relationship to any human pathology. By contrast with stunting models, appropriately crafted protocols that produce a negative nitrogen balance in rodents, albeit by means of dietary nitrogen levels uncharacteristic of human consumption patterns, nevertheless reproduce the diagnostic features of kwashiorkor in weanlings (e.g., [ 16 ]) and produce the depressed inflammatory immune competence (e.g., [ 9 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]) and susceptibility to opportunistic and other infections [ 17 , 19 , 21 , 23 , 24 , 25 , 26 , 27 ] that characterize the human pathology.…”

“…Complete diets for rodents are sufficiently nitrogen-rich that, apart from the occasional strategy of acute withdrawal of all nutrients except water, a regimen sometimes imposed on adult animals (e.g., [ 38 , 39 ]) but not on weanlings, even the most extreme restricted intake protocol elicits a caloric deficit without imposing a deficiency of protein (e.g., [ 40 , 41 ]). By contrast, some low-protein diet protocols reduce food consumption sufficiently to induce a concomitant caloric deficit (e.g., [ 22 , 40 , 41 , 42 ]), whereas others appear to produce an exclusive nitrogen insufficiency (e.g., [ 11 , 16 , 21 , 43 ]). Occasionally, restricted intake of a nitrogen-deficient diet is imposed to ensure a combined deficit of both protein and calories [ 7 , 44 , 45 ].…”

“…In turn, the unexpected robustness of naïve-phenotype T cell populations in the face of catabolic malnutrition gave rise to studies of dendritic cells because of the unique potency of these antigen presenting elements for activating the naïve T cell. Ultimately, this pursuit generated a challenge to the classic T cell-centric focus of the research front by placing the dendritic cell and antigen presentation at the center of malnutrition-associated inflammatory immune depression [ 22 , 72 ].…”

“…Intervention studies involving metabolically diverse forms of acute, experimental malnutrition reveal that infectious disease resistance and components of both innate and adaptive inflammatory immune competence can be sustained, or even restored, independently of ongoing weight loss and in the face of profound lymphoid involution [ 20 , 25 , 38 , 39 , 42 , 78 ] even at the weanling stage of life [ 18 , 22 , 31 , 64 , 72 , 79 , 80 ]. With two exceptions, one an intervention with a bacterial culture condensate [ 78 ] and the other an adoptive transfer design [ 22 ], these studies demonstrate responsiveness to endocrine hormones and cytokines on the part of immunological elements and functions, in vivo , even during advanced stages of experimental malnutrition pathology. Importantly, the studies span three endocrine hormones (the glucocorticoids, leptin and triiodothyronine) and four hematopoietic cytokines (granulocyte, macrophage and granulocyte-macrophage colony-stimulating factors and fms-like tyrosine kinase 3 ligand), seven independent research groups and eight distinct rodent models of acute malnutrition.…”