Critical Developmental Windows For The Immune System In Rodents

The developmental progression of cells, sequential migration of immature cells to a series of embryonic tissue sites, and differences in hematopoietic microenvironments in each of these tissue sites (Figure 1.3) strongly suggests that different periods of embryonic development may be differentially susceptible to immunotoxic insult. For that reason, a hypothetical sequence of windows of vulnerability for the developing immune system was recently proposed (Dietert et al. 2000). Details of this scheme as they apply to rodent development are presented in Figure 1.4 of this chapter and include five critical windows of potential vulnerability. Embryonic development does not proceed in lock-step sequence, and these windows of vulnerability are clearly not discrete. However, even though there is a considerable overlap of these developmental windows, they are based on a set of unique developmental events that can be followed in temporal sequence and describe the initial appearance of specific immunohematopoietic cell types or specific immune functions during embryonic and postnatal development in rodent species.

Birth

Stem Cell Formation

Tissue

Migration &

Progenitor Cell Expansion

Bone Marrow and Thymus Maturation

Days of Gestation

17.5

Figure 1.3 Critical periods in development of immune function in rodents.

Development of the Rodent Immune System

day 7-9

day 9-16

day 13-birth

birth-day 30

day SC-day 60

Initiation of Hemato-poiesis

Migration of Stem Cells and Expansion of Progenitor Cells

Colonization of Bone Marrow and Thymus

Maturation to Immunocom-petence

Establishment of Immune Memory

Maturity

rth Sexual

Figure 1.4 Critical windows of vulnerability to environmental insult during development of the rodent immune system.

The first critical window (gestational days 7 to 9) is characterized by initial organogenesis of the hematolymphoid system from undifferentiated mesenchymal cells (Fehling et al. 2003) and generation of sufficient HSC to initiate both blood formation and immunity (Cumano et al. 2000). Damage to this process of initial stem cell formation is likely to have dramatic and persistent effects during the remainder of development and during postnatal life. The second critical window (gestational days 9 to16) represents a period of extensive migration of HSC to new tissue environments, generation and expansion of lineage-specific progenitor cells for leukocytes, and organogenesis of secondary lymphoid tissues (Godin and Cumano 2002). It is intriguing that the absence of lymphoid cell progenitors during this critical period results in the failure of secondary lymphoid tissues to develop (Godin and Cumano 2002). This suggests that secondary systemic failures of the immune system result from failure of hematopoietic cell development due to the requirement for these cells in induction of vascular budding and secondary lymphoid organ formation.

The third critical window described (gestational days 13 to birth) is dominated by ossification of bone, formation of bone marrow, and colonization of this marrow space by hematopoietic stem cells and the spectrum of hematopoietic progenitor cells (Dietert et al. 2000). Bone marrow is the hematopoeitic organ that persists throughout postnatal life, and immunotoxic damage during this critical period of transition for the hematopoietic system and establishment of the bone marrow has the potential for lasting effects on both blood cell development and immune function.

There are two critical periods of immune system development that follow birth in rodents. For the first month of life, the spleen persists as a hematopoietic organ and immune responses have a characteristic immature nature, characterized by the failure of rodents to respond to carbohydrate antigens (Tavassoli and Yoffey 1983). Rodents share this period of perinatal immunodeficiency with other mammals (including humans) and damage to lymphoid organs or cells during this period has the unique potential to result in lifelong damage to immune function. And finally, the initiation of normal mature immune responses to environmental pathogens and antigens during the first few months of life is essential to development of a set of memory lymphocytes that maintain immunocompetence following senescence of primary lymphoid organs.

These five critical windows of developmental vulnerability provide a working framework for the design of experiments aiming to test immunotoxicity of environmental agents on rodents. It will be essential to test both acute toxicity of these agents at each developmental stage and the potential for acute damage to persist into postnatal life.

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