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1
Introduction
Each of the rodent strains and mutants described in this volume has some
defect in immunity. Some of the deficiencies, like that which occurs in the
nude mouse, are caused by single point mutations; others are complex ab-
normalities involving multiple genes. Some of the mutations are allelic;
others, although exhibiting similar pathologic processes, are not. The ability
to establish these mutations in inbred strains and to develop congenic lines
has greatly enhanced the usefulness of these models and fostered a better
understanding of mutant gene effects. New techniques, such as DNA cloning
and sequencing, have allowed investigators to define precisely the biochem-
ical defect in several mutations. However, when these animals are used, an
understanding of mechanisms for ensuring genetic purity and a knowledge
of standardized nomenclature are essential.
The purpose of this volume is to summarize and furnish key references
on the genetics, pathophysiology, husbandry, and reproduction of various
immunodeficient rodent strains and mutants. To aid the reader in evaluating
these models, the organization and function of the mammalian immune sys-
tem are reviewed, and pertinent information on both gene markers and stan-
dardized nomenclature is provided. In addition, the role of environmental
factors on normal immunologic functions is discussed.
Several of the mutants considered in this volume require strict isolation
from infectious agents, and one chapter (Chapter 4) is devoted to detailing
isolation procedures. Special approaches are necessary to propagate some of
the mutants, and another chapter (Chapter 5) discusses various mating sys-
tems. Finally, the information in this document has been extracted from a
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2 IMMUNODEFICIENT RODENTS
body of literature spanning 20 years of research in immunology. Naturally,
during that time many synonyms and acronyms have emerged, and the def-
initions of certain terms have been refined. To assist the reader with these
terms, the committee has prepared a table (see the Appendix) organizing the
rodent lymphocyte differentiation antigens into currently known cluster des-
ignation groups and a glossary, arranged by abbreviation followed by the
complete name of each term.
IMMUNE SYSTEM FUNCTION
Host Defense Systems
.
All mammals live in a sea of microorganisms, which includes bacteria,
fungi, viruses, rickettsia, protozoa, and multicellular parasites. Many of these
organisms have the capacity to replicate within the animal's body and cause
disease; however, they are prevented from establishing an infection by a
complex system of interacting innate and adaptive immune mechanisms. The
innate defense system includes the integrity of the skin and mucous mem-
branes; mucous secretions; cilia of epithelial cells on mucous membranes,
which generate a mucous stream; nonspecific inflammatory processes; phago-
cytic cells; large granular lymphocytes, which function as natural killer cells;
and biologically active molecules, such as histamine, complement, and other
acute-phase reactants. Innate defense mechanisms can act alone to prevent
the introduction of infectious agents into the body or to survey the tissues
for newly arising neoplastic cells that, once recognized, are attacked. These
nonspecific mechanisms also interact with specific (adaptive) immune mech-
anisms by processing foreign material prior to its presentation to lymphoid
cells (afferent phase), amplifying relevant clones of lymphoid cells (central
phase), and assisting in the delivery of an immune-mediated attack on foreign
particles (efferent phase). When an infectious agent successfully breaches
the innate defense system, the adaptive immune system is activated to mount
an attack that is specific to the invading agent. A mechanism of immunologic
memory in the adaptive immune system enhances the protection of the host
against subsequent assaults by the same agent.
The Nature of Adaptive Immunity
Through eons of selection, vertebrates have evolved a system of interacting
cells and molecular substances that operate in a coordinated fashion to deliver
an attack of exquisite specificity. This high degree of specificity is often
necessary to direct effecter cells and substances against targeted agents with-
out also damaging bystander cells and tissues. However, in order to achieve
this degree of specificity, two major obstacles must first be overcome. The
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INTROD UCTION 3
first is the requirement for a system that can generate an enormous number
of unique recognition sites capable of binding to the myriad of potentially
harmful agents that animals encounter on a daily basis. The second obstacle
is to confine the action of this system to elements, both cellular and molecular,
that are foreign to the host. The adaptive immune system has developed
novel and very complex solutions to these problems.
The great complexity involved in generating immunologic specificity af-
fords opportunities for errors to arise in the system. These errors, although
relatively rare, are frequently devastating to the host. They may be char-
acterized by the inability of the host to eliminate or neutralize foreign sub-
stances (immunodeficiency) or the failure to discriminate between self and
nonself (autoimmunity). ~
The adaptive immune system is composed of various functionally distinct
cells and their products. Cells of the lymphoid series play a principal role
and are characterized by the presence on the cell surface of distinct glyco-
peptides that serve as developmental markers and functional receptors. Post-
natally, pluripotential hematopoietic stem cells reside in the bone marrow.
Certain committed lymphocyte precursors home to the thymus, where they
interact with thymic stromal cells and subsequently emerge as mature T cells,
expressing new surface markers (differentiation antigens). Surface molecules
on lymphocytes can be used to identify functional subpopulations of cells or
stages of maturation. Many of the surface glycoproteins of T cells play a
key role in cell-to-cell communication and in antigen recognition. Various
T cells are known to assist or suppress antibody synthesis by another set of
lymphocytes, B cells, or to engage in cytotoxic activity. T cells are the major
cell type involved in the defense against virus-infected cells, the rejection
of allogeneic cells and tissues, and delayed-type hypersensitivity reactions.
B cells differentiate along a pathway distinct from that for T cells and
express their own unique surface molecules. B cells produce immunoglobulin
or antibody. Each B cell is genetically precommitted to the production of
antibody with a defined structure and, therefore, with a defined specificity.
When a B cell proliferates, foxing a clone, its daughter cells make precisely
the same antibody. As a B cell matures, it expresses a specific cell-surface
receptor for antigen. This receptor and the immunoglobulin that the B cell
will secrete at maturity have similar molecular structures and identical binding
specificities. There is a third group of cells, including dendritic and Lan-
gerhans' cells and monocyte-macrophages, that function by presenting an-
tigen to T cells.
Once antibody is produced, it interacts with antigen and a variety of
nonspecific factors (i.e., complement, polymorphonuclear leukocytes, and
mast cells) that make up the innate defense system. These innate defense
system components direct and magnify the neutralizing effects of antibody
on a specifically targeted foreign substance. The recruitment of various non
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4 IMMUNODEFICIENT RODENTS
specific factors in the efferent phase of the immune response greatly amplifies
the activity of antibody and is crucial for the development of effective bodily
defenses. An example of this interaction between antibody and a nonspecific
defense system is the activation of the complement pathway.
The complement system is characterized by an array of peptides, proen-
zymes, enzymes, receptors, and biologically active effecter molecules. This
system, which is made up of a minimum of 20 components, interacts through
at least two separate pathways (cascades, to achieve a major biological am-
plification of the action of specific antibody molecules. The fragments of
several of these peptides enhance phagocytosis and chemotaxis and alter
vascular permeability. The formation of a membrane attack complex (a com-
plex molecule composed of five complement components) on the surface of
a eukaryotic cell induces a structural alteration of the plasma membrane,
resulting in cytolysis. A similar mechanism has been shown to be effective
on some prokaryotic cells. The complement system, operating in conjunction
with other components of the innate immune system (i.e., segmented neu-
trophils and other host systems, including the coagulation and fibrinolytic
enzyme systems), can induce an acute inflammatory response in areas of
microbial invasion.
Immunologic Specificity
The specificity imparted on the adaptive immune system involves the
production and surface display of receptors capable of binding unique epi-
topes found on foreign cells, microbes, and substances. Structurally different
but functionally similar receptors are found on B and T lymphocytes. Each
mature B cell has a surface receptor that is encoded by the same genes as
the immunoglobulin it is capable of secreting. It is estimated that more than
1 million different immunoglobulin molecules are produced by the B cells
of individual mice and humans (and most likely all other mammalian species).
When fully differentiated, each B lymphocyte is equipped to produce anti-
body molecules with a single specificity. This is accomplished by a mech-
anism of gene rearrangement that occurs during B-cell maturation.
Immunoglobulin molecules (Figure 1-1) are glycoproteins with a basic
four-chain structure composed of two large heavy chains, which are cova-
lently linked by disulfide bonds, and two smaller light chains, which are
attached to the heavy chains by disulfide bonds. The region where heavy
chains are united is called the hinge region. Each heavy chain is composed
of four subunits or domains that share amino acid homology. Three of these
domains have a relatively constant sequence of amino acids, but the fourth,
an N-terminal domain, contains a region where the amino acid sequence is
variable (between different B cells). Immunoglobulin light chains have two
domains: The COOH-terminal domain is constant in amino acid composition;
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INTROD UCTION 5
Antigen
Binding
Sites
Vet
CH1`
Renion ~
Disulphide
Bond
__!
-
Heavy Chain
~ 450 Residues
`~ Carbohydrate
Light Chain
~ 212 Residues
FIGURE 1-1 The basic structure of IgG. The amino-terminal end is characterized by sequence
variability (V) in both the heavy (H) and light (L) chains, which are referred to as the VH and
Vie regions, respectively. The rest of the molecule has a relatively constant (C) structure. The
constant portion of the light chain is termed the Cat region. The constant portion of the heavy
chain is further divided into three structurally discrete regions: CH1, CH2, and CH3. These
globular regions, which are stabilized by intrachain disulfide bonds, are referred to as domains.
The sites at which the antibody binds antigen are located in the variable domains. The hinge
region is a vaguely defined segment of heavy chain between the CH1 and CH2 domains.
Flexibility in this area permits variation in the distance between the two antigen-binding sites,
allowing them to operate independently. Carbohydrate moieties are attached to the CH2 do-
mains. Source: Roitt et al. (1985). Reprinted courtesy of Professor Roitt, Dr. Brostoff, Dr.
Male, and Gower Medical Publishing.
the N-terminal domain is variable. There are five different classes (isotypes)
of immunoglobulin (Ig): IgM, IgG, IgA, IgE, and IgD. The IgG class of
immunoglobulin in humans, mice, and rats can be broken down into four
subclasses, while that in hamsters and guinea pigs has only two known
subclasses. Subclasses of IgA are found in humans, mice, and rabbits. Class
and subclass distinctions arise from common amino acid sequences found in
the heavy chains. In addition, each species has both kappa and lambda light
chains, again based on common amino acid sequences. Because immuno-
globulin molecules are secreted intact from a B lymphocyte, both heavy
chains are identical, and likewise, both light chains are identical. The des-
ignation of subclasses and the concentrations of various classes of immu-
noglobulins vary among mammalian species. Generally, one type of light-
chain class predominates in a species. In rats, guinea pigs, mice, and humans
the predominant light chain is the kappa chain; in dogs, cats, and horses it
is the lambda chain.
Each of the immunoglobulin classes and subclasses has a distinct distri-
bution in the fluid compartments of the body and a distinct function in host
defense. The heavy chains of different antibody molecules contain different
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6 IMMUNODEFICIENT RODENTS
chemical determinants in the constant and hinge regions of the molecule that
activate the complement system, determine the attachment site for antibody
on cells, and control the distribution of antibody through the placenta or yolk
sac to the embryo.
The genetic mechanism r~.~non~ibl~ for the trPmPnr1ml~c A;~/D'~;~! ~( arm.
body molecules involves rearrangement of genes for constant (C) regions
and variable (V) regions in both the light and heavy chains. Genes that
contribute to the peptide sequence of V regions are deployed along the same
chromosome that encodes the C regions of each chain. Between the V- and
C-region genes are joining (J) and, in some cases, diversity (D) region genes.
Genetic sequences encoding for the human kappa-chain C and V regions are
on chromosome 2, for the lambda-chain C and V regions are on chromosome
22, and for the heavy-chain C and V regions are on chromo.~om~. 14 The
~AVOWS_ ^~4 BAA_ ~AAA_lA~V~LO -1 V ~1 all V ~1 ~llL1
_ _1 1~ , 1 ~ ~
genes encoding for the kappa-, lambda-, and heavy-chain C and V regions
of mice are located on chromosomes 6, 16, and 12, respectively. The order
of gene sequences found on mouse chromosome 12 is S'--V--D--J--~-~-~y3-
)/1,]/2b,)/2a~~~~~CX~~3'. The various gene regions found distal to the J region
(toward the 3' end of the DNA) make up the C-region sequences. Specificity
and function of heavy chains are determined by the combination of genes
selected from the V, D, J. and C regions. The process involved in coordi-
nating these genetic rearrangements is still not completely understood.
Heavy-chain genes are first to rearrange. This involves joining of a di-
versity (-D) with a J gene, followed by joining of this DJ complex to one of
the many V-region genes. Finally the three-member complex VDJ is tran-
scribed as a unit into RNA and, during RNA processing, is spliced adjacent
to the C-region genes. The mu (~) gene for the heavy-chain C region is the
first to be chosen. Later in B-cell development, one of the other C-region
genes might be chosen through a complex gene switching process.
In both humans and mice, kappa-chain genes are rearranged before lambda-
chain genes. Rearrangement of the lambda-chain genes is initiated whenever
a given cell fails to make a functional rearrangement at either of its two
kappa-chain alleles. After VJ joining occurs, a gene for the C region is
selected and light-chain gene expression follows.
Antibody gene rearrangement takes place during the early phases of B-
cell differentiation. Once a functional gene rearrangement has occurred within
one light- and one heavy-chain cluster, the specificities of both antibody and
surface receptor are fixed through the process of allelic exclusion. This
mechanism ensures that a B cell will express an immunoglobulin molecule
composed of a single light and a single heavy chain. At this point the B cell
is ready to bind antigen through its membrane-inserted surface immuno-
globulin. Antigen binding is the first in a series of complex steps that lead
to the selective proliferation of the B cell and its clonal expansion. Binding
of antigen to surface immunoglobulin sets in motion a series of events that
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INTROD UCTION 7
include differentiation, as well as proliferation, immunoglobulin secretion,
isotype switching, and the generation of immunologic memory. Macro-
phages, T cells, and lymphokines can influence the differentiation of B cells.
The surface membrane-inserted T-cell antigen receptor (Ti or TCR) is
similar to the B-cell antibody. The Ti receptor is a heterodimer, which in
most cells is an alpha (a) and a beta (~) chain generated at different stages
of T-cell differentiation and inserted through the plasma membrane. A small
population of T cells uses a Ti receptor composed of a gamma (^y) and a
delta (~) chain. The Ti receptor is closely associated with a group of T-cell
surface molecules collectively called T3. The Ti and T3 glycopeptides appear
to work together in the activation of T cells following antigen binding to Ti.
The generation of the Ti receptor uses complex genetic rearrangements of
variable-region determinants, which allows for receptor diversity and spec-
ificity. The basic mechanism of joining V, D, and C regions is similar to
that seen for immunoglobulin heavy chains. The Ti)-chain gene develops
from multiple germline variable-region genes (V~) and adjoining sets of
diversity IDA,, DQ2), joining AJAR, Jim), and constant ICES, CQ2) gene seg-
ments. The Tia-chain gene consists of multiple Vet genes, at least 40 Jot
genes, and one constant C`x gene.
The T-cell genes rearrange in an ordered fashion, beginning with the Tiy-
and Ti8-chain genes and progressing through the Tin- and TiQ-chain genes.
The function of cells with Ti receptors composed of By and ~ chains remains
unclear. The location of the Ti receptor-chain genes includes chromosomes
14 (a and 8), 6 All, and 13 lays in mice. Binding of antigen to a specific Ti
receptor is the initial step leading to the generation of clones of fully dif-
ferentiated T cells. T cells, unlike B cells, do not secrete a soluble form of
their antigen receptor.
T cells fall into two or more distinct subpopulations based on functional
criteria. T cells, upon maturation, express either helper-inducer or cytotoxic
functions and are called Th and Tc cells, respectively. T cells, unlike B cells,
are not readily triggered by soluble antigens. Even multimeric antigens or
antigens bound to an insoluble matrix are poor stimulators of T cells. In
practice, T cells are activated only by antigens associated with the surface
of other cells; that is, to be effective, antigen must be "presented" to T
cells. The requirements for successful presentation are under intense study,
but it is thought that antigen or antigen fragments are effective T-cell acti-
vators only when they are bound to certain presenting cell-surface molecules,
in particular, to major histocompatibility complex (MHC) antigens. MHC
antigens are responsible for evoking tissue rejection responses. Class I MHC
antigens are found on all nucleated cells and are composed of a 45-kilodalton
(kDa) polypeptide chain and a 12-kDa chain. The latter, a F2 microglobulin,
is highly conserved, while the larger chain is encoded by members of a large
gene family with extensive polymorphism. Class II MHC antigens (Ia an
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8 IMMUNODEFICIENT RODENTS
tigers) are composed of 28-kDa and 32-kDa subunits. Their expression is
limited to antigen-presenting cells, including B cells, macrophages, and den-
dritic cells. In humans, but not in mice, Ia antigens are also expressed on T
cells.
Afferent, Central, and Efferent Limbs of the Immune System
The sequence of events that occur from the moment a foreign substance
enters the body until it is destroyed or neutralized is highly coordinated and
involves both nonspecific and specific immune defenses. To aid in the de-
scription of the events confronting the immune system, scientists have des-
ignated all events occurring before the activation of T and B lymphocytes
as the afferent phase, all activities involving the specific interaction of antigen
with lymphocytes as the central phase, and the activity of effecter mechanisms
in neutralizing or destroying the foreign substance as the efferent phase.
Foreign substances or pathogenic microorganisms sometimes elude the
host's physical barriers and enter the body at several different sites. The
major portals of entry are the skin (integument) and mucous membranes. It
is not surprising, therefore, to discover that specialized defense systems,
including immunologic defenses, have been established to deal with intru-
sions at these sites. Both the skin and mucous membranes are richly endowed
with lymphatics that drain to regional lymph nodes. In addition, specialized
lymphoid structures, that is, the tonsils, Peyer's patches, and appendix, are
found at various sites associated with mucosal surfaces. These are referred
to collectively as mucosa-associated lymphoid tissue (MALT). The skin is
rich in a variety of specialized cells (mast cells, Langerhans' cells, indeter-
minate cells, and veiled cells) that participate in immune system function.
The last three cell types are known to participate in antigen presentation.
Adherent Limb
Organisms newly introduced into a host are initially confronted by cir-
culating monocytes, macrophages, specific T and B cells, neutrophils, or,
in the skin, Langerhans' cells. Some of these cells participate in phagocytosis
and degradation (neutrophils, macrophages), and others are nonphagocytic
and participate chiefly in antigen presentation (Langerhans' and other den-
dritic cells). Organisms also enter the lymphatics, either directly or following
partial digestion by phagocytes, where they are transported to regional lymph
nodes, to MALT, or to both. Foreign substances introduced into the blood
confront the reticuloendothelial system, which comprises the spleen, blood
vessel endothelium, alveolar macrophages, and Kupffer cells of the liver.
The cumulative events that occur from the moment an organism breaches a
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INTROD UCTION 9
primary barrier until it is processed, transported, and presented to lympho-
cytes comprise the afferent limb of the immune system.
Central Limb
During the central phase of the immune response, there is an antigen-
induced activation of either specific T-cell or B-cell clones or both. For those
antigens that require T- and B-cell interactions to achieve antibody synthesis,
T lymphocytes must recognize class II MHC antigens on the surface of
antigen-presenting cells. This two-point recognition system, that is, foreign
antigen and MHC determinants, allows T and B cells to come into close
apposition. Stimulation of Th cells results in the secretion of lymphocyte
growth factors interleukin-2 (IL-2), IL-4, and IL-S, which, together with
foreign antigen, can induce B-cell proliferation. In this manner the Th cell
provides a positive signal that allows for the selective proliferation of a clone
of B cells preselected by the specificity for and binding to foreign antigen.
Clonal proliferation then results in an expanded population of B cells. Some
of these undergo terminal differentiation and produce antibody, in part be-
cause of the effects of the lymphokines y-interferon and IL-6. Others are
available for future clonal proliferation. This latter population of B cells
provides the basis for immunologic memory and the secondary immune
response. Similarly, T cells, following binding to Ia-associated antigen, pro-
duce T-cell growth factors (IL-2 and IL-4) and express the appropriate re-
ceptors for them.
It has been postulated that another T cell, the Ts cell, can also be specif-
ically activated in a manner similar to that of Th cells. In contrast to Th
cells, the Ts cell is thought to secrete a variety of suppressor substances that
interfere with B-cell activation and diminish the production of antibody.
The cytotoxic T cell can be activated by mechanisms similar to those
described above. This cell enters the circulation in search of a target cell that
displays a determinant recognized by its receptor. Its ability to bind and
liberate cytocidal substances requires a recognition of antigen in association
with class I MHC antigen determinants.
EJj~erent Limb
As previously mentioned, the binding of antibody to foreign antigen results
in a conformational change in the antibody molecule, thus producing an
activation site for the first component of complement. The sequential acti-
vation of the complement system via the classical pathway generates bio-
logically effective split products that assist in mediating local inflammation.
The systemic activation of complement can result in a more injurious acti-
vation of the kinin and coagulation pathways, culminating in shock. Com
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10 IMMUNODEFICIENT RODENTS
plexes of antigen, antibody, and complement are removed quickly from the
circulation by cells bearing either Fc receptors, which bind the constant region
of IgG or IgM, or complement receptors, which bind the activated products
of complement (e.g., CR11.
Antibody-dependent cytotoxic cells (ADCC) are lymphocytes or mono-
cytes that bear the Fc receptor for antibody heavy chains. These cells become
armed with specific antibodies and deliver a combined assault known as
antibody-dependent cellular cytotoxicity on targeted cells. Similarly, hom-
ocytotropic (IgE) antibodies bind mast cells and basophils. Degranulation
tales place following the binding of foreign antigen to these cells, resulting
in the release of histamine, heparin, and other mediators of inflammation.
This mast cell-mediated mechanism is thought to be important in the ex-
pulsion of endoparasites from the gastrointestinal tract.
Natural killer (NK) cells apparently recognize and destroy cells (e.g.,
cancer cells or virus-infected cells) nonspecifically. Some NK cells are large,
granular lymphocytes of uncertain lineage. Others are descended from Tc
cells and bear T-cell surface differentiation antigens and both Ti and T3.
For all three phases of the immune system to operate normally, a wide
variety of other humoral immune modulators must interact properly with cells
of both the nonspecific defense system and the immune system. T cells, for
instance, are known to have receptors for estrogen. The binding of estrogen
to this receptor generates a signal that enhances immunity. NK cells have a
dependency on serotonin, which is present in circulating platelets. All cells
have receptors for insulin, growth hormone, and thyroxine, and the involve-
ment of these hormones is necessary for properly functioning host defenses.
Lymphocytes have receptors for glucocorticoids, which are immunosup-
pressive. In addition, lymphocytes can have receptors for Q-endorphin, pro-
lactin, histamine, calcitonin, and Q-adrenergic substances. Receptors for
1,25-dihydroxyvitamin D3 are not present on resting lymphocytes but are
synthesized during lymphocyte activation. Although a precise role for many
of these ho~ones has not been defined, each potentially has an immuno-
modulating activity.
Immunodeficiency
Compromises in host defenses involve the defective function of either
specific immunity or the nonspecific defense mechanisms. The defects in
any of the three functional phases of the immune system (afferent, central,
or efferent) can compromise immune-mediated defenses. Defects in the im-
munologic defenses can be either primary or secondary. Primary defects are
usually genetically determined, and secondary deficiencies result from de-
velopmental abnormalities, environmental factors, or as consequences of
microbial action. Both primary and secondary immunodeficiencies compro
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INTROD UCTION 11
mise greatly the capacity of mammalian hosts to live successfully in a mi-
crobe-laden environment.
Primary genetic deficiencies of immunity are rather infrequent as individual
abnormalities; however, they are not rare when considered in the aggregate.
Indeed, they make up an important component of the inborn errors of me-
tabolism. Secondary immunodeficiencies of humans and animals, occurring
as the consequence of malnutrition, cancer, environmental or pharmacologic
intoxication, metabolic disorders, pathologic processes, or aging, are among
the most frequent underlying causes of serious life-threatening diseases.
The immunodeficiencies of rodents and humans can be visualized in the
context of genetic deficiencies in any of several functional components of
the immunologic defenses. For purposes of classifying the disorders of im-
mune function, one attempts to define the major immunologic cell systems
that are primarily involved. The integrity of primary tissues responsible for
lymphocyte development (thymus and bone marrow), the precise lymphoid
cell population or subpopulation absent or perturbed in development, the
nonspecific cellular defense involved in an abnormality, the molecular basis
of the defect, and, finally, the precise genetic basis of the compromised
immunologic function are all important in the final classification. Some of
the most impressive insights into immunologic arrangements and function
have been discovered by studying immunocompromised rodents.
EFFECT OF ENVIRONMENTAL FACTORS ON
IMMUNE FUNCTION
Investigators interested in probing the immune system must be aware that
certain environmental factors, both infectious and noninfectious, can lead to
a transient immune suppression or stimulation. Such factors complicate re-
search results, regardless of whether the animal is normal or immunodefi-
cient, and should be avoided.
Noninfectious Agents
Various agents have been associated with changes in the function of the
immune system in rodents, including diet, stress, and drugs. Dietary con-
taminants such as lead and cadmium increase the susceptibility of rodents to
infectious diseases (Hemphill et al., 1971; Cook et al., 19751. Cadmium, in
particular, has been associated with suppression of interferon production
(Blakley et al., 1980) and abnormalities in macrophage function (Loose et
al., 1978a). Abnormalities in both lymphocyte and macrophage activity have
been reported in rodents drinking hyperchlorinated acidified water (Fidler,
1977; Hermann et al., 1982J.
Various factors that ultimately cause stress in rodents can impair immu
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32 IMMUNODEFICIENT RODENTS
LG I LG 11
._
1 0
B
_ Rip-2
Tbm-1
Prt- 1
2 P
_ M-1
1 3
6
9
30
A
1 .
Lap-1
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c RT4
f7T-6
Hbb ~
4 Ma /-2 8s
2 fz . - b
Rw
Ldr-1-
w
hd
19
Hras.- 1
Chromosome 1
8
~ _
1 3
Sh
an
Cu-1
, ia
- Map- 1
[film- 1J
- Acon- 1
26
~ _st
LG 111 LG IV LG V
8
20 .
- Tbm-2
- Gox-1 ~
s
7
3
- Mdl-1 ~
4 - a
~ Svp
1 6
2
t7T9
t? T2
Es-2,4,8, 10
Es -3, 7, 9
Es- 1, 14, 1 5,
16, 18
FIGURE 1-3 Linkage map of the rat, which is based on literature and recent unpublished
information. Except where indicated. the linkages shown have not yet been assigned to chro-
mosomes. An enlargement of RTI is given below linkage group IX ("*"). Linkage data for
Es-6, Ir-JHM, RT3, and Tbm-2 have been established by recombinant inbred strain analysis.
Brackets indicate that the position of one of the two genes with respect to other genes within
this linkage group has not been verified. The assignment of linkage groups I, VIII. and IX to
chromosomes 1, 6, and 14, respectively, is based on Levan et al. (1986). Map compiled by
H. J. Hedrich, Central Institute for Laboratory Animal Breeding, Hannover, Federal Republic
of Germany (1988).
Gc 5
10
s
1 6
- h
_ sib_
~ Es-6 g
_ lx
. RTS
_ Glo-1
_ Acry-1 26
_ PiTI
Igh-1
~ Igh-2
Chromosome 6
12
' .
32
1 0
0.5
1 0
_ -PiT1.A
_ -R T 1 D |
l -Bf
_ -PIT1.C
0.072
*
Chromosome 14
-RT1. E
w-3
INTRODUCTION 33
LG Vl LG Vll LG Vlil LG IX LG X LG X1
Len-1
RT3 _
Pep-3 _ .
Fh
A hd-c
Eag-1
_ - C6
- Akp-1
34 IMMUNODEFICIENT RODENTS
In general, the rules of standardized nomenclature followed for all the
commonly used laboratory rodents are those prepared by the International
Committee on Standardized Genetic Nomenclature for Mice. The most recent
version of these rules will be available shortly for both mice (Lyon, in press)
and rats (Greenhouse et al., in press). Updates of the rules are printed
periodically in Mouse News Letter, which is published by Oxford University
Press, Walton Street, Oxford OX2 6DP, England, and in Rat News Letter,
which is edited and printed by Dr. Donald V. Cramer, 712 Scaife Hall,
University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
In designating hybrids (the first-generation offspring of a cross between
two inbred strains), it is customary to list the female parent first. Thus, the
first-generation offspring of a cross between a C57BL/6J female and a
C3H/HeJ male is written C57BL/6J x C3H/HeJ Fit or, if necessary for clarity,
(C57BL/6J x C3H/HeJ)F~. The filial generation (F) number is written as a
subscript to distinguish it from the strain and substrain designations. Once
the hybrid has been fully described in this manner, an abbreviation may be
used thereafter to save time and space. If an abbreviation is used, it should
be appended to the initial designation, for example, C57BL/6J x C3H/HeJ
Fit (hereafter called B6C3F~. A list of abbreviations for inbred strains can
be found in Staats (19811.
No sources are given for the immunodeficient rodents discussed in this
report because of the rapidly changing nature of commercial and research
animal colony holdings. To locate these models, contact the Animal Models
and Genetic Stocks Information Program of the Institute of Laboratory An-
imal Resources, National Research Council, 2101 Constitution Avenue. NW
Washington, DC 20418 (202-334-25901.
GENERAL READING
~ _ , . . . .
The following general references provide information on the topics dis
cussed in this report:
Altman, P. L., and D. D. Katz, eds. 1979. Inbred and Genetically Defined
Strains of Laboratory Animals. Part 1. Mouse and Rat. Bethesda, Md.:
Federation of American Societies for Experimental Biology. 418 pp.
Benjamin, E., and S. Leskowitz. 1988. Immunology: A Short Course. New
York: A. R. Liss. 328 pp.
Feldman, D. B., and J. C. Seely. 1988. Necropsy Guide: Rodents and the
Rabbit. Boca Raton, Fla.: CRC Press. 167 pp.
Fogh, J., and B. C. Giovanella, eds. 1978, 1982. The Nude Mouse in
Experimental and Clinical Research. New York: Academic Press. 1978,
vol. 1, 502 pp.; 1982, vol. 2, 587 pp.
Gershwin, M. E., and E. L. Cooper, eds. 1978. Animal Models of Com
INTROD UCTION 35
parative and Developmental Aspects of Immunity and Disease. New York:
Pergamon. 396 pp.
Gershwin, M. E., and B. Merchant, eds. 1981. Immunologic Defects in
Laboratory Animals. New York: Plenum. Vol. 1, 360 pp.; vol. 2, 382 pp.
Gill, T. J., III, H. W. Kunz, D. N. Misra, and A. L. Cortese-Hassett. 1987.
The major histocompatibility complex of the rat. Transplantation 43:773-
785.
Green, E. L., ed. 1966. Biology of the Laboratory Mouse, 2nd ed. New
York: McGraw-Hill. 706 pp.
Green, E. L. 1981. Genetics and Probability in Animal Breeding Experi-
ments. New York: Oxford University Press. 271 pp.
Green, E. L., and D. P. Doolittle. 1963. Systems of mating used in mam-
malian genetics. Pp. 3-41 in Methodology in Mammalian Genetics, W. J.
Burdett, ed. San Francisco: Holden-Day.
Hedrich, H. J., ed. In press. Genetic Monitoring of Inbred Strains of Rats.
A Manual on Colony Management, Basic Monitoring Techniques, and
Genetic Variants of the Laboratory Rat. Stuttgart: Gustav Fischer Verlag.
Klein, J. 1982. Immunology: The Science of Self-Nonself Discrimination.
New York: John Wiley & Sons. 687 pp.
Klein, J. 1986. Natural History of the Major Histocompatibility Complex.
New York: Wiley Interscience. 775 pp.
Lyon, M. F. 1963. Genetics of the mouse. Pp. 199-234 in Animals for
Research. Principles of Breeding and Management, W. Lane-Petter, ed.
London: Academic Press.
Lyon, M. F., and A. G. Searle, eds. In press. Genetic Variants and Strains
of the Laboratory Mouse, 2nd ed. Oxford: Oxford University Press.
Paul, W. E. 1984. Fundamental Immunology. New York: Raven Press.
809 pp.
Reed, N. D. 1982. Proceedings of the Third International Workshop on Nude
Mice. Vol. 1: Invited Lectures, Infection, Immunology; 330 pp. Vol. 2:
Oncology; 690 pp. New York: Gustav Fischer.
Roitt, I., J. Brostoff, and D. Male. 1985. Immunology. London: C. V.
Mosby, Gower Medical. 300 pp.
Salzman, L. A. 1986. Animal Models of Retrovirus Infection and Their
Relationship to AIDS. Orlando, Fla.: Academic Press. 470 pp.
Shultz, L. D., and C. L. Sidman. 1987. Genetically determined murine
models of immunodeficiency. Annul Rev. Immunol. 5:367-403.
Sordat, B., ed. 1984. Immune-Deficient Animals. Basel: S. Karger. 445 pp.
Theofilopoulos, A. N., and F. J. Dixon. 1985. Murine models of systemic
lupus erythematosus. Adv. Immunol. 37:269-390.
