==== Front
Exp AnimExp. AnimEXPANIMExperimental Animals1341-13571881-7122Japanese Association for Laboratory Animal Science 2941591017-015010.1538/expanim.17-0150ReviewComparative immunity of antigen recognition, differentiation, and other
functional molecules: similarities and differences among common marmosets, humans, and
mice Kametani Yoshie 1Shiina Takashi 1Suzuki Ryuji 2Sasaki Erika 3Habu Sonoko 41) Department of Molecular Life Sciences, Tokai University
School of Medicine, 143 Shimokasuya, Isehara-shi, Kanagawa 259-1193, Japan2) Department of Rheumatology and Clinical Immunology, Clinical
Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National
Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara-shi, Kanagawa 252-0392,
Japan3) Central Institute for Experimental Animals,3-25-12
Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-0821, Japan4) Department of Immunology, Juntendo University School of
Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanAddresses corresponding: Y. Kametani, Department of Molecular Life Sciences, Tokai
University School of Medicine, 143 Shimokasuya, Isehara-shi, Kanagawa 259-1193,
Japan8 2 2018 2018 67 3 301 312 26 11 2017 16 1 2018 ©2018 Japanese Association for Laboratory Animal
Science2018This is an open-access article distributed under the terms of the Creative
Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0:

https://creativecommons.org/licenses/by-nc-nd/4.0/)The common marmoset (CM; Callithrix jacchus) is a small New World monkey
with a high rate of pregnancy and is maintained in closed colonies as an experimental
animal species. Although CMs are used for immunological research, such as studies of
autoimmune disease and infectious disease, their immunological characteristics are less
defined than those of other nonhuman primates. We and others have analyzed antigen
recognition-related molecules, the development of hematopoietic stem cells (HSCs), and the
molecules involved in the immune response. CMs systemically express Caja-G, a major
histocompatibility complex class I molecule, and the ortholog of HLA-G, a suppressive
nonclassical HLA class I molecule. HSCs express CD117, while CD34 is not essential for
multipotency. CD117+ cells developed into all hematopoietic cell lineages, but compared
with human HSCs, B cells did not extensively develop when HSCs were transplanted into an
immunodeficient mouse. Although autoimmune models have been successfully established,
sensitization of CMs with some bacteria induced a low protective immunity. In CMs, B cells
were observed in the periphery, but IgG levels were very low compared with those in humans
and mice. This evidence suggests that CM immunity is partially suppressed systemically.
Such immune regulation might benefit pregnancy in CMs, which normally deliver dizygotic
twins, the placentae of which are fused and the immune cells of which are mixed. In this
review, we describe the CM immune system and discuss the possibility of using CMs as a
model of human immunity.

antigen recognitioncommon marmosethematopoietic stem cellimmune system
==== Body
Introduction
Nonhuman primates (NHPs) play a pivotal role in basic brain science and clinical research
of the central nervous system. They have also been used as infectious disease models and in
research on reproduction. However, the immune system has not been as well studied as the
nervous system in NHPs at the molecular level. Using rodents as experimental animals, many
molecular aspects of the human immune system have been explained and predicted, but it has
also been clarified that the human and mouse have significant differences [48]. The reason why the research concerning immunity in
NHPs, which are more akin to humans, is behind that in rodents is mainly the level of
research tools. For example, there are many inbred lines for rodents, specifically mice,
that possess a homozygous background for not only major histocompatibility complexes (MHCs)
but also for genes encoding other proteins. Immune research in rodents involves a large
number of analytical tools, such as specific antibodies against NHP species-specific
antigens. Without these tools, no classical transplantation experiments would be successful.
NHPs for which completely genotypically homozygous animals have not been established cannot
match the extent to which rodents are used in immunology research. This might be a major
reason why extensive comparisons of NHP immune function with mouse and human immune function
have not been conducted, especially for the function of immune regulation. Cynomolgus
monkeys are one of the most extensively studied NHPs. Recently, MHC-identified monkeys were
obtained [2, 5,
37]. This made transplantation-based immunological
research possible [36, 51]; however, MHC-homologous animals are very limited, so researchers
cannot frequently use them for transplantation-based immunological research. Molecularly
targeted drugs, such as neoantigen-specific monoclonal antibodies, require preclinical
studies involving NHPs. However, even among primates, antigen-recognizing molecules are
highly evolved and branched. Therefore, responses do not completely mimic the human response
[85]. These limitations for the prediction of
antigen recognition by human immune cells using NHPs may lead to low reliability when using
them as a model for human immunology. Therefore, while the importance of NHPs for
preclinical studies of moleculary targeted drugs is increasing, our understanding of the
basis of molecular immunity is still relatively immature. To better understand the
immunological characteristics of human immune responses to molecularly targeted drugs, we
must select adequate species among the various experimental animals, which will enable
reliable translational research. Thus, it is urgent to clarify the characteristics of the
immune system of each primate species and to select adequate species for various types of
studies.

Callithrix jacchus is conventionally known as the common marmoset (CM)
[43, 44] and
is a New World monkey for which colonies have been established via planned breeding. Closed
CM colonies have been maintained in Japan for approximately 50 years. CMs diverged from
humans approximately 33 million years ago (MYA), which was after the divergence of rats and
mice (diverged by 96 MYA) and before the divergence of macaques (diverged by 23 MYA), which
are the most widely used model species in the study of motor systems [54, 87]. CMs are small and possess
a high reproductive capacity, conceiving 2–3 offspring per pregnancy twice a year. Because
of these advantages, Japanese researchers at the Central Institute for Experimental Animals
(CIEA, Kawasaki, Japan) succeeded in the establishment of transgenic animals and in
performing gene targeting of these animals [72, 73]. Transgenic CMs have shown promise in playing an
important role in primate brain research and research on neuronal diseases because the CM
brain is the simplest and smallest among the available experimental primates [49, 57].

With regards to CM immunity, there are several previously reported research models. For
example, there are models of infectious diseases [15,
62], autoimmune disorders [1, 6, 30, 84], and transplantation
immunology [64, 86]. CMs are susceptible to natural infections with particular strains of
bacteria, which are thought to be caused by their diminished MHC class II repertoire [3, 18, 83]. However, these factors, which result in a unique
immune system, have not been well characterized. Caja-G genes were
identified as the main MHC genes of CMs, and a polymorphism indicates that
Caja-G plays a role in the activation of cytotoxic T cells in a manner similar to classical
MHC class I molecules, which are known to activate cytotoxic T cells that specifically react
to infectious microbes. However, polymorphic MHC molecules might not recognize the T cell
receptor (TCR) of CMs in a manner similar to class I HLAs, including HLA-A, HLA-B, and
HLA-C, as Caja-G is an ortholog of HLA-G, an immune suppressing nonclassical HLA. Thus, the
susceptible nature of CMs to some strains of bacteria may also indicate that the function of
the CM immune system is dampened not only by malfunctioning MHC class II molecules but also
by its unique MHC class I structure.

Because CMs are New World monkeys that diverged relatively early in primate evolution, they
possess one of the oldest sets of immune characteristics common in primates. On the other
hand, protein sequences included in CM immunity shares only a limited similarity with
humans. We and others have examined the cross-reactivities of various anti-human monoclonal
antibodies and demonstrated that a large part of the antibodies did not react with CM
antigens [7, 26, 29]. To identify molecules useful for
examining the immune system, we prepared CM antigen-specific monoclonal antibodies and
simultaneously identified the immune-related cDNAs [33, 39]. Subsequently, we performed
analyses of CM immunity. Limitations in analytical tools prevent a more detailed analysis of
the CM immune system; however, we obtained some intriguing results. In this review, we will
describe the CM immune system and discuss its potential as an experimental animal, which
thus far mimics human immunity.

Homology of Immune-related Genes
The evolution of immune system-related genes is relatively unique because it involves not
only various functional molecules but also MHC molecules, TCRs, and immunoglobulins (Igs),
which all evolved rapidly in divergent directions [19, 69]. While the variability of effector
molecules, including cytokines and surface receptors such as cytokine receptors, toll-like
receptors, and integrins, reflects the complexity of the immune function of a species, the
variability of MHC molecules, TCRs, and Igs determines the capacity for antigen recognition.
These molecules are indices of what type of antigen the species can recognize and what kind
of regulatory systems the species possesses to recognize antigens. Primates are not an
exception. As MHC molecules, TCRs and Igs have evolved in order to recognize non-self
antigens, it is possible that environmentally closely related species possess more highly
conserved sequences. Collectively, the molecules involved in immune effector functions and
those involved in antigen recognition should be analyzed independently. The structures of
these molecules also suggest that while molecules working on immune effector function
include various families and can be discussed in parallel with other nonimmune molecules,
the molecules involved in antigen recognition have unique and repetitive sequences and
should be evaluated independently.

Therefore, we first analyzed the cDNA sequences for these molecules, which have immune
effector functions that involve cytokines, and we compared their homologies with mouse and
human sequences [39]. From our results, an 86 ± 5.5%
homology was observed between CM and human cDNA sequences. The homology of the same gene set
between humans and mice was 61 ± 13% and that between CMs and mice was 60 ± 13%; therefore,
CM genes appear to be much closer to human genes than to mouse genes.

As for the MHC molecules of CMs, Caja genes, which are equivalent to
HLA class I genes, contain Caja-B, Caja-G, and Caja-F
loci [77]. Shiina et al. determined
the structure of Caja-B and Caja-G genes. The
Caja-G gene cluster contains 14 loci, and at least 5 loci express
functional gene products [40]. It has recently been
shown that multiple alleles can be found at these loci [3, 9, 53, 83]. Examining the homology of
Caja genes and HLA genes shows that
Caja-G has a high homology with HLA-G, suggesting that
they are evolutionarily closely related, as shown in Fig.
1Fig. 1. Phylogenetic tree of MHC class I molecules in humans and common marmosets. HLA-G
orthologs (beige squares), HLA-F orthologs (pale blue squares), and HLA-B orthologs
(pink squares) are shown in the phylogenetic tree. The LBP and the scale of the
substitutions/site are shown. Caja-G, HLA-G, and HLA-A diverged recently.

. Similarly, Caja-F is highly related to HLA-F, and
Caja-B is related to HLA-B, while HLA
orthologs have not been identified in rodents.

It is well known that HLA-G is a nonclassical MHC molecule, and is represented by only one
locus in humans, with a low number of alleles, and is expressed mainly on the placenta and
by regulatory T cells. HLA-G is reported to suppress the immune system [10]. In contrast to HLA-G, Caja-G is systemically
expressed and polymorphic, similar to the characteristics of human classical class I HLAs.
This raises the question of what function Caja-G molecules perform. While the peptide
presentation of the HLA-G and the ortholog has now been identified [50, 53], it is unclear if it
possesses a sufficient repertoire to interact with anchoring peptides derived from numerous
pathogens. Therefore, it may be helpful to examine the following three hypotheses. (1)
Because HLA-G has the potential to present many types of peptides, Caja-G, as the ortholog
of HLA-G, may present such peptides and activate the immune system in a manner similar to
classical MHC class I molecules. (2) Caja-G may suppress the immune system in a manner
similar to HLA-G through orthologs of HLA-G ligands. (3) Caja-G may contain both classical
class I-like loci and nonclassical class I-like loci, and their functions may be divergent.
Clarifying the functions of Caja-G is one of the most important issues for understanding the
acquired immune system of CMs. For example, it would be beneficial to better identify the
MHC molecules exclusively expressed on trophoblasts of the placenta because, in humans,
HLA-G is mainly expressed on extravillous trophoblasts and prevents maternal immunity from
rejecting the semi-allogeneic fetus [16].

In CMs, the presence of the genes for LILRB1 and LILRB2 orthologs, which are HLA-G ligands
[12,13,14, 67], is
predicted. These ligands might interact with HLA-G and suppress the activation of T cells
and natural killer (NK) cells [12, 14]. However, the ortholog of KIR2DL4, which plays a
pivotal role in the placenta, has not been predicted [68]. Thus, the identification of loci for Caja-G, the products of
which suppress immune function in a manner similar to HLA-G, as well as the identification
of relevant ligands, is important. If immune-suppressive MHC molecules are located on all
tissues, we would not be able to use CMs as a model animal for research on human
transplantation immunology.

Although we have not analyzed MHC class II molecules, Antunes and colleagues reported that
HLA-DR and HLA-DQ of CMs are functional but that their diversity is small [3]. Plasad et al. reported the divergence
of Caja-DRB and, specifically, the identification of
DRB*W16 [64, 65]. Similar to Caja-B, as reported by Shiina et al.
[77], classical HLA class II orthologs in CMs also
appear to function similarly to human HLAs.

In contrast to these findings, the homology of the TCR repertoire is high between CMs and
humans. Dr. Suzuki’s group reported that most of the genes for TCR repertoires possessed a
greater than 90% homology in the CDR3-FR4 region, and none of the repertories possessed less
than 80% homology in the CDR3-FR4 region between CMs and humans [38, 46]. No reports have yet
identified the sequence homology of Igs.

Collectively, (1) individual molecules related to immune function in CMs show a greater
homology to humans than to mice; (2)Caja genes in CMs have been identified
as orthologs of HLAs but are unique in having more loci and fewer alleles than those in
humans; and (3) the TCR in CMs is evolutionarily close to that in humans. In other words,
the factors of immune function common in both mice and humans are also common in CMs, while
the molecular structures of antigen-recognizing molecules in CMs are more closely related to
humans.

Differentiation of Immune Cells
To characterize immune cells, identification of the developmental pathway is important.
Hematopoietic cells of humans and rodents have been identified using an SRC assay in
immunodeficient mouse systems [17, 41, 61, 89]. Subsequently, evidence has been accumulating for the
repopulation and development of human immune cells. CD117 and Sca-1 are hematopoietic stem
cell (HSC) markers in mice, and CD34 has been revealed to be an HSC marker in humans [22, 56]. CD34 is
also expressed on hematopoietic progenitor cell lines in mice [4]. However, HSCs of New World monkeys have not been identified.
Therefore, we established an anti-CM CD34 monoclonal antibody and anti-CM CD117 monoclonal
antibody, and identified CD117 as a CM HSC marker using these antibodies [29, 33]. Next, we
examined if the multipotency and developmental pathway of CM HSCs were similar to those of
humans by transplanting the cells into severely immunodeficient NOG mice [27, 55, 78]. CM bone mallow cells were collected from newborn CMs
that were abandoned due to a birth of triplets. The cells were stained with monoclonal
antibodies, which we established [33], anti-CD117, as
a mouse HSC marker, and anti-CD34, as a human HSC marker [24, 48, 56, 59]. The cells were sorted in
accordance with the expression of both markers using a cell sorter and subjected to a colony
or SRC assay using immunodeficient NOG mice [27,
28, 32,
45]. The engrafted cells were analyzed using flow
cytometry, and their engraftment capacity and ability to differentiate were measured.
Consequently, we found that (1) CM CD117+ cells developed into erythroid and myeloid
lineages when the colony assay was conducted, independent of CD34 expression. (2) The SRC
assay revealed that CD117+ cells developed into T cells and B cells in NOG mice. (3) CD117+
cells developed into mast cells both in vitro and in NOG mice [55, 78], (4) CD8 T
cells but not B cells predominantly developed after HSC transplantation, and (5)
multipotency, evaluated by SRC assay, showed that total engraftment in NOG mice after HSC
transplantation was enhanced by CD34 expression. No CD4 T cells were observed in the SRC
assay. As previously reported, when human HSCs were transplanted into NOG mice, B cell
development preceded T cell development, and CD4 T cells and CD8 T cells developed
simultaneously [27, 32, 45, 90]. This evidence suggests that the developmental pathways are different between
CMs and humans. NOG mice developed not only CM lymphoid cells but also CM myeloid cells,
represented by mast cells, early after the transplantation of HSCs into NOG mice [78]. The CM-transplanted NOG mice expressed the cDNAs of
various CM cytokines, suggesting that these CM cells were somewhat functional.

A study of HSC development from embryonic stem cells (ESCs) was reported by Sasaki
et al. [71]. They introduced
Tal1/Scl genes, which encode essential transcription factors in normal
and malignant hematopoiesis in humans [63] into CM
ESCs, and found that the cells highly expressed CD34. Although CD34 is not an HSC marker of
CMs, according to our results, it is probable that Tal1/Scl-transfected
ESCs have characteristics of a hematopoietic lineage and contain HSCs. In parallel with
these results, Izawa et al. (2004) [29] and our group (2008) [78] observed the
multilineage differentiation of CD34+ cells in NOD/SCID and NOG mice. Schrimpf et
al. succeeded in the development of neutrophils from induced pluripotent stem
(iPS) cell-derived hematopoietic cells expressing CD34 [75]. The function of CD34 has been studied, and functions correlated with adhesion
and proliferation inhibition have been reported [81].
However, the function of CD34 in hematopoiesis has not been completely described until
recently. Therefore, it is difficult to interpret the meaning of the differences in CD34
expression among mice, CMs, and humans. The mechanisms of migration and localization of HSCs
might be different among species.

On the other hand, immune cells are nearly completely deficient in NOG and NSG mice [27], both of which lack IL-2Rγ signaling in the NOD/SCID
background. IL-2Rγ plays a pivotal role in the development of lymphocytes [42]. However, if a mouse has only IL-2Rγ
gene deficiency [8, 9] but is not bred in the NOD/SCID background, then the effect is less severe,
although B cell development is suppressed and T cell development is delayed. Sato and our
group established IL-2Rγ-knockout (KO) CMs using a genome-editing method
and found that IL-2Rγ-KO CMs showed a deficiency in IL-2Rγ chain-related
cytokine signaling, which induced a less severe immunodeficiency in CMs than in humans, and
T cells developed later, similar to findings in IL-2Rγ-KO mice [73]. B cells were not observed in adult peripheral blood
mononuclear cells (PBMCs) of IL-2Rγ-KO CMs. T cells expressed the molecule,
which cross-reacted with a human CD56 antibody. Wild-type CMs also expressed a CD56-like
molecule, and the expression level of each cell was higher than in KO CMs. Although it is
unclear why the cells expressed the CD56-like molecule, these features might be important in
CM immune function.

These results suggest that CD117 is expressed on HSCs of CMs, which is similar to mice, but
the fact that CD34-expressing cells possess high potential for engraftment indicates a
similarity with humans. Therefore, CM IL-2Rγ possesses a function similar to that in mice,
although there have been reports of patients with severities of immunodeficiency similar to
those observed in mice and CMs [74]. Collectively, in
the mouse environment, CM HSCs showed a unique development of lymphoid cells, as B cell
development in CMs is delayed compared with that in humans.

Function of Immune Cells
In CM PBMCs, both helper T (Th) cells and cytotoxic T (Tc) cells exist similarly to those
in mouse and human PBMCs. However, the ratio of Tc cells tends to be high, as is frequently
observed in other NHPs. Most of the cytokines produced by mice and humans are observed in
CMs, and the production of the mRNAs is enhanced after T cell stimulation. CM PBMCs were
prepared and stimulated with PMA/ionomycin or the super-antigen toxic shock syndrome toxin-1
(TSST-1) [79]. Before and after stimulation, mRNA
levels were measured by quantitative RT-PCR. Consequently, the transcription of most of the
cytokines was enhanced [21, 33]. However, in CMs, the increase in IL-4 mRNA levels
was lower than in humans, and the IFN-γ levels were higher, suggesting that
immunity shifted to cellular immunity or a Th1-type response. From this perspective, the CM
cytokine environment preserves a type typical of NHPs and is different from that of modern
humans [31].

We also analyzed the phenotype of NK cells [88]. If
we accept the cross-reactivity of human anti-CD56 monoclonal antibodies in CMs, CD56
molecules were not expressed on resting NK cells, and after stimulation with IL-2, activated
NK cells expressed CD56. These cells also expressed NKG2D and possessed killer activity.
These results suggested that NK cells are prepared for activation in the CM immune response.
Moreover, there is another class of NK cells, known as uterine NK (uNK) cells, that have no
cytotoxic activity but secrete cytokines and are involved in the development of placental
cells. They react with unique ligands such as KIR2Dl4 in humans. However, as we described
above, genes for KIR2DL4 orthologs have not been identified, indicating the
absence of this molecule in CMs. These findings suggest that CMs do not preserve the
function to remodel blood vessels of the placenta as observed in humans [68]. Thus, CM uNK cells might be different from those of
humans and other primates [60].

Normally, humoral immunity involves complements and Igs. Complements are categorized as
natural immunity-related molecules, and Igs are categorized as acquired immunity-related
molecules. Interestingly, CM plasma contains complement components according to an LC/MS
analysis (report in preparation). Moreover, they were detected in the lesions of CMs with
experimental autoimmune encephalomyelitis (EAE) [82]
Therefore, natural humoral immunity in CMs might be similar to that in other primates and
rodents. Moreover, the acquired humoral immunity of CMs is highly unique. The amount of Igs
in the plasma is extremely low, as Igs were hardly detected by LC/MS (report in
preparation), although a significant amount of B cells was detected in PBMCs. Importantly,
IgG was scarcely observed, although some IgM was detected, while human and mouse sera
contain detectable levels of IgG. Moreover, germinal centers were not observed in the spleen
or lymph nodes (LNs) (Fig. 2Fig. 2. HE staining of common marmoset spleen tissue. Representative data of a
hematoxylin-eosin-stained spleen section (6-year-old female CM). The right panel shows
a magnified image of the left panel (black open square). No clear germinal centers
were observed in the spleen section.

), while it is well known that several germinal centers are detectable in the head of
the spleen in mice under specific pathogen-free conditions. This evidence is comparable with
the findings reported by Quint et al. showing that IgG levels were much
lower than IgM levels after xeno-stimulation in vitro, even if antibody
production was somewhat enhanced. Such evidence is not similar to findings for humans and
mice [66]. For NHP vaccination models, macaques are
usually used because they can secrete antigen-specific IgGs. However, CMs might not be
suitable for use as a vaccination model in place of macaques. This does not conflict with
the fact that many infection models have been established using CMs but that the
vaccinations tested were not effective. Griffiths et al. reported
vaccination-induced antigen-specific IgM and IgG production, but they also reported that the
antigen types that induced an immune response were limited [23]. It is a unique condition compared with conventional primate and rodent
acquired immunity. For example, robust antibody production was observed against an anthrax
protective antigen and a whole-cell pertussis vaccine, while weaker responses were obtained
against cholera and typhoid vaccines. Moreover, the increase in titers was not always
extensive. Thus, the overall efficiency of the immune response of CMs might be considered to
be significantly lower than in humans.

To investigate the mechanism underlying multiple sclerosis (MS), a CM EAE model was
established [34]. After extensive analysis of this
useful model, the importance of B cells was suggested by treatment with an anti-human CD20
monoclonal antibody [35], although the model showed a
heterogeneous response to the treatment due to its outbred nature. The specific role of B
cells in this process has yet to be clarified.

Collectively, immune function in the periphery of CMs might be different from that of
humans and mice. They may have a unique function of immune suppression, specifically in
their humoral immunity.

Discussion and Perspective
We summarized the characteristics of CM immune factors in Table 1Table 1. Comparison of immune-related molecules among human/CM/mouse species
		human	CM	mouse	reference for CM	reference for mouse and human (review)	
Antigen Recognition limit						
	classical MHC class I	HLA-A,B,C	Caja-B, G (?)	H-2K,D,L	[9, 40, 53,
77, 83]	[47, 76]	
	non-classical MHC class I	HLA-E,F,G	Caja-F,G (?)	Qa-1, 2	[40, 53]	[10, 16, 50,
76] 	
	class II MHC	HLA-DR, DQ	Caja-DRB	I-A, E	[3, 64, 65]	[47, 76]	
	TCR	(+)	(+)	(+)	[38, 46]	[11]	
	Serum IgM	(+)	(+)	(+)	[66]	[58]	
	Serum IgG	(+)	(±)	(+)	[66, 73] 	
functional moleculesfor immune
activation						
	LILRB1	(+)	(+ ) predicted	NKG2A	*XM_017967588.1
*XM_017967590.1
*XM_017967591.1
*XM_017967592.1
*XM_017967589.1	[12, 13, 14, 52,
67, 68]	
	LILRB2	(+)	(+) predicted		*XM_017969139.1 		
	NKG2D	(+)	(+)	(+)	[88]		
	KIR2DL4	(+)	(−)	(−)	No predicted sequences were found in NCBI		
	complement	(+)	(+)	(+)	[82]	[20, 70]	
Differentiation						
	HSC marker	CD34	CD117	CD117	[29, 78]	[17, 22, 41,
56, 61, 89]	
	IL-2Rg KO effect	severe T/B deficiency	B cell deficiency	B cell deficiency	[73]	[8, 9, 74]	
	B cell /T cell order	B prior to T 	simultaneous (CD8Tl)		[78]	[27, 32, 45,
90]	
*NCBI reference sequence.

. CM immune function is predicted to be evolutionally intermediate to that of
mice and humans as far as the homology of immune-related genes except antigen
recognition-related genes (MHC molecules, Igs and TCRs) was concerned. Genes for these
antigen-recognizing molecules have evolved uniquely. They have many loci, but their
diversity in CMs is rather small compared with that in humans. The nonclassical
HLA-G ortholog has many loci and is expressed in the body. The
developmental process of lymphocytes is also unique, as B cell development is suppressed or
delayed in immunodeficient NOG mice compared with that in humans. Moreover, Tc cells tend to
be more abundant than Th cells. However, these findings do not conflict with the fact that
humoral immunity related to Th2 cytokines is down-regulated in the periphery of CMs. The
delay of B cell development and the suppression of Th cells might reduce B cell activation,
reducing the secretion of antigen-specific antibodies and class switching of IgM antibodies
to IgG and IgE antibodies, resulting in the suppression of IgG-based humoral immunity.
Moreover, if Caja-G, which is expressed throughout the body, induces suppressive signals
into immune cells, as does HLA-G, these peripheral immune functions might be suppressed
systemically.

This finding might correlate with the uniqueness of pregnancy in CMs, which normally
deliver dizygotic twins [25]. The placentae of these
twins are fused, and their immune cells are mixed with each other, but no rejection of the
two allogeneic sets of tissue is induced [80]. The
detailed mechanism for this is unclear. If the CM immune system cannot reject any allogeneic
tissues, then fusion and maintenance of the allogeneic placentae may be possible.

This evidence suggests that wild-type CMs in a closed colony may not easily be developed as
a model relevant to Th2 immunity. If we need such models, the establishment of Th2
cytokine-overexpressing transgenic CMs, such as IL-4-Tg-expressing animals,
may help to lead to a breakthrough. Otherwise, we need to more strictly select the target
phenomenon or disease. Macaques and other Old World monkeys may have an immune system more
closely related to the human immune system. However, the molecules for antigen recognition
have diverged from those of humans, like those of CMs. Moreover, fertility is less efficient
than in CMs, which is a limitation of Old World monkeys as experimental animals. These
findings should be considered when using NHP species. The characteristics of NHPs, including
CMs, should be studied in greater detail to select the experimental animals beneficial for
the preclinical examination of molecularly targeted drugs.

This work was supported by the Japan Society for the Promotion of Science by a Grant-in-
Aid for Scientific Research (C) (grant number 25430095 to Yoshie Kametani), a Tokai
University Grant-in-Aid to Yoshie Kametani (2013–2014), and the MEXT-Supported Program for
the Strategic Research Foundation at Private Universities (2012–2016).
==== Refs
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