Download From Immunity and Vaccines to Mammalian

SUPPLEMENT ARTICLE
From Immunity and Vaccines to Mammalian
Regeneration
Ellen Heber-Katza
The Wistar Institute, Philadelphia, Pennsylvania
Our current understanding of major histocompatibility complex (MHC)-mediated antigen presentation in self
and nonself immune recognition was derived from immunological studies of autoimmunity and virus-host interactions, respectively. The trimolecular complex of the MHC molecule, antigen, and T-cell receptor accounts
for the phenomena of immunodominance and MHC degeneracy in both types of responses and constrains vaccine development. Out of such considerations, we developed a simple peptide vaccine construct that obviates
immunodominance, resulting in a broadly protective T-cell response in the absence of antibody. In the course of
autoimmunity studies, we identified the MRL mouse strain as a mammalian model of amphibian-like regeneration. A significant level of DNA damage in the cells from this mouse pointed to the role of the cell cycle checkpoint gene CDKN1a, or p21cip1/waf1. The MRL mouse has highly reduced levels of this molecule, and a genetic
knockout of this single gene in otherwise nonregenerating strains led to an MRL-type regenerative response,
indicating that the ability to regenerate has not been lost during evolution.
Keywords. CDKN1a; comets; HSV gD; immunodominance; peptide-palmitic acid; mammalian regeneration;
MRL mouse; trimolecular complex; p21cip1/waf1; vaccine.
The role of just plain luck and being in the right place
at the right time must never be discounted in science.
The studies presented in this article arose out of just
such personal circumstances. The laboratory of Robert
E. Click, at the University of Wisconsin–Madison, pioneered the important role of reducing agents in lymphocyte culture to study T-cell and B-cell collaboration for
antibody responses. The laboratory of Darcy B. Wilson,
at the University of Pennsylvania, was one of the first to
focus on the allogenic histocompatibility responses of
T cells in vitro and in vivo. The laboratories of William
Paul, Ron Schwartz, and Ethan Shevach, at the Laboratory of Immunology, National Institute of Allergy and
Infectious Diseases, were ground zero for T-cell and
major histocompatibility complex (MHC) studies. Finally, The Wistar Institute, under the great Hilary
a
Present address: Lankenau Institute of Medical Research, 100 E Lancaster Ave,
Wynnewood, PA 19096 ([email protected]).
Correspondence: Ellen Heber-Katz, PhD, The Wistar Institute, 3601 Spruce St,
Philadelphia, PA 19104 ([email protected]).
The Journal of Infectious Diseases® 2015;212(S1):S52–8
© The Author 2015. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
DOI: 10.1093/infdis/jiu637
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Koprowski, who encouraged immunity studies in the
context of live viral responses (always with an eye in
the direction of vaccines) instead of the more usually
studied peptide model antigens, was central to the dissection of immunodominance for vaccines and the
search for the effects of autoimmunity on normal biology. It is from this perspective that the studies presented
below should be viewed.
RESULTS AND DISCUSSION
Studies in Immunology and Vaccines
After having shown that the antigen-presenting cell,
through its MHC class Ia molecule, displayed different
antigen-presenting capacities and thus strongly suggested that peptide antigens could bind differently to the
MHC molecule [1–5], I came to The Wistar Institute
to continue my studies on the recognition of antigen
( pigeon cytochrome c as a model antigen) by T cells
as defined by the trimolecular complex (Figure 1). The
major difference was that the studies at Wistar were directed at multiple disease models instead of a model antigen in which to test the response to self versus nonself
and the role of the MHC molecule. The environment
that was created was based on Dr Koprowski’s focus
Figure 1. This model of T-cell receptor (TcR) recognition of antigen
shows specific, named interaction sites on the antigen (epitope interacts
with TcR; agretope interacts with the major histocompatibility complex
[MHC] class Ia molecule), the MHC class Ia molecule on the antigenpresenting cell (APC; desetope interacts with antigen, and histotope
interacts with TcR), and the TcR for antigen, referred to as the trimolecular
complex. The antigen shown is the pigeon cytochrome c fragment 81–104.
This predated the MHC-peptide crystal structure. Reprinted from [5].
on (1) neurotropic viruses and related autoimmune central nervous system (CNS) diseases and (2) vaccine production.
For responses to so-called self antigens, we examined the autoimmune response to myelin basic protein, a CNS-derived
molecule that could induce encephalomyelitis when injected
into rodents and produce disease symptoms with some similarity to those of multiple sclerosis [6–8]. We found T-cell response differences related to the particular MHC recognized
that were similar to those we had shown with cytochrome c.
Thus, different peptides would stimulate different T-cell clones,
depending on the MHC class Ia molecule used. Furthermore,
we identified T-cell receptors (TcRs) that were used by pathogenic T cells, which we described as the “V region disease hypothesis” [9–20]. This specifically defined Vβ8, Vα2, and Vα4
as regions used by pathogenic T cells. In addition to these
findings and in support of our theory, subsequent genetic
mapping of a diabetes susceptibility gene proved to be a TcR
V region [21].
For responses to so-called nonself antigens, we examined
the T-cell response to herpes simplex virus type 1 (HSV-1)
and HSV-2. Dr Koprowski was interested in HSV as a latent
virus that might be the cause of multiple sclerosis or other
CNS diseases. Nigel Frasier was at The Wister Institute studying
HSV latency. Also, studies of the N-terminal 1–23 amino acid
antigenic peptide of HSV glycoprotein D (gD) were already ongoing in the laboratories of Bernhard Diestzschold and Elaine
DeFreitas at The Wistar Institute, in collaboration with Gary
Cohen and Roz Eisenberg at the University of Pennsylvania.
We joined the HSV group and began our studies on gD antigen
presentation. We found that the N-terminal gD peptides could
induce MHC class Ia–related changes in T-cell specificity [22–
25]. Thus, responses to self and nonself displayed the same
MHC class Ia–specific responses.
Immundominance, the induction of specific peptide responses after priming with a whole protein molecule, was directly
related to the specific MHC class Ia molecule used for antigen
presentation. We had generated a full set of consecutive gD peptide 20-mers plus a set of peptides with 10 amino acids overlapping between each peptide. We tested multiple strains of mice
with different MHCs and found that, after whole gD recombinant protein immunization in complete Freund adjuvant
Figure 2. Peptide vaccine constructs induce protection. Peptides derived from glycoprotein D (gD) of herpes simplex virus (HSV) were generated as
consecutive 20 amino acid peptides, and each was coupled to palmitic acid. These were incorporated into liposomes and injected into BALB/c mice in
complete Freund adjuvant (CFA). The mice were then infected 2 months later with HSV type 2, the level of protected was analyzed. None of the peptides
were shown to be immunodominant. Three of the peptides showed 80%–100% survival among mice. Three of the peptides showed 10%–50% survival.
None of the mice that received the CFA control survived (not shown).
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(CFA), each evaluated strain (with a different MHC class Ia molecule) showed different gD peptide responses. Interestingly, none
of those peptides were 1–23. We then asked whether infectious
HSV-induced immunity gave the same or different responses.
To our surprise, all of the peptides could stimulate T cells derived
from such mice. Thus, virus infection could overcome immunodominance [26, 27]. Could this be important for vaccine
development?
We thought that this knowledge should be useful for the
production of a peptide vaccine. There was an interest in the scientific community about using fatty acids to link peptides to cell
surfaces. Also, in previous experiments at the National Institutes
of Health, we showed that antigens associated with lipid produced strong T-cell responses in the absence of a B-cell response.
Could we then produce a vaccine that was specifically T-cell
inducing and protective? We first tested peptide alone, and
there was no protection against HSV infection. We tested 1–23
peptide coupled to palmitic acid, and it also was not protective.
However, 1–23 peptide couple with palmitic acid, when incorporated into a liposome and then CFA, produced long-lived protection against HSV-1 and HSV-2, without a B-cell or antibody
response. We found that the best fatty acid proved to be palmitic
acid and that all components of the vaccine were necessary. In
fact, leaving out any of the components led to suppression of protection. Furthermore, splenic cell transfer of protection was accomplished and required a CD8+ population [28, 29].
If the 1–23 peptide as our vaccine construct could induce
protection but was not immunodominant, then maybe any
HSV peptide in such a construct could induce protection. We
had previously produced overlapping peptides along the length
of the HSV gD molecule to examine fine specificity and immunodominance. We furthermore made the same peptides with
palmitic acid attached. We produced vaccine constructs for
the first 6 consecutive peptides attached to palmitic acid, incorporated the constructs into liposomes, and injected them in
CFA. These were not immunodominant (ie, injection of gD protein in CFA into BALB/c mice did not induce a response to any
of these peptides), but we predicted that all of the peptides would
induce protection when configured in our vaccine construct.
BALB/c mice were then immunized with each of these 6 peptide
vaccines. As seen in Figure 2, some level of protection was seen
with every peptide vaccine (US patent 5 837 249).
Creating a functional, strongly protective vaccine that will
work in the vast majority of the unselected vaccinated population is both an art and a science. Dr Koprowski, of course, was a
master of the craft. However, the best vaccines are still variants
of Jenner’s cowpox/smallpox killed or attenuated whole virus.
With the emergence of human immunodeficiency virus
(HIV) and Ebola virus, for instance, the risk of manufacture,
let alone administration, of killed or attenuated whole-virus vaccines may be too high for general acceptance. Is it possible
to achieve a level of protection equivalent to that of killed/
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Figure 3. The MRL/lpr mouse has been used as a model of systemic
lupus erythematosus. When ear punching to number the mice, we noticed
that after 1 month, the ear-punched hole disappeared without evidence of
scarring, with regrowth of hair follicles and cartilage; cartilage usually
takes an additional 2 months to regenerate. This ear hole response predicted the unusual healing response seen both in the MRL/lpr and MRL/MpJ
in multiple organs and provided a quantitative and easily accessible trait
useful in genetic mapping studies.
attenuated virus vaccines with a wholly synthetic vaccine that
overcomes the limitation of immunodominance? We believe
so and have patented a long-since-abandoned generic structure
of such a vaccine. Sadly, it was never pursued. However, the science and methods are now free to anyone who wants to use
them. Finally and most intriguing is the possibility that antibody might confound the protective response in infections
due to pathogens such as HIV and Ebola virus, and this
T cell-inducing vaccine might prove significant.
Figure 4. Evidence of G2/M arrest in MRL cells (B), compared with
C57BL/6 (B6) cells (A) is clear and consistent with other regenerating
(LG/J; healer congenics) versus nonregenerating (SM/J) mouse models.
Besides evidence of a DNA damage response (data not shown), actual
DNA damage is obvious, using a comet assay, in MRL cells (D), compared
with B6 cells (C).
Studies in Regeneration
Out of our studies in autoimmunity, we found that the MRL/lpr
mouse, used as a spontaneous model of systemic lupus erythematosus that we were using for drug studies, showed an unusual
healing ability. Thus, when we punched ears to number them,
instead of providing a long-lived marker, the holes closed up
without scarring and virtually disappeared (Figure 3) [30].
This was noticed by Lise Clark, a postdoctoral fellow who
came to my laboratory from Will Silvers’ laboratory and was
yet another person from the Koprowski–Wistar Institute lineage. This ear punch experiment was repeated in MRL/lpr and
MRL/MpJ mice, and we realized there was something quite
unique about these mice. This was an opportunity we could
not pass up.
We explored multiple tissue types in the adult MRL/MpJ
mouse for their regenerative ability, including heart [31–33],
CNS (such as spinal cord, brain, and optic nerve) [34–36], cartilage [37], and digits [38], and found that this was not just a
local effect but was animal wide.
The cells derived from MRL ear tissue also displayed many
unique properties. Not surprisingly, cells from the regenerating
MRL mouse ears grew quite rapidly, while cells from nonregenerators, including almost all other mouse strains, grew very
slowly. An analysis of the cell cycle properties of these cell
lines showed that, unlike the slow-growing nonregenerative
cells, the regenerative cells displayed a large percentage of the
population in the G2 phase, potentially in arrest (Figure 4A
and 4B). This suggested that there was an ongoing DNA damage response. In consultation with The Wistar Institute cell
Figure 5. Evidence for lack of CDKN1a ( p21cip1/waf1) protein and its effect in p21 knockout mice. A, A Western blot of cells from MRL and B6
mouse ears and human HCT cells shows expression of p21 before and
after γ irradiation (γIR). In B6 and HCT cells, p21 protein is present, and
levels increased after irradiation. In MRL cells, p21 is absent. B, Cell cycle
analysis shows G2M arrest in ear cells derived from p21 knockout mice,
unlike the control. C and D, Examination of ear hole closure in control
mice (C) and p21 knockout mice (D) shows that elimination of p21 leads
to ear hole closure.
cycle guru, Thanos Halazonetis, we examined the protein levels
of p53, phosphorylated H2AX, and the DNA repair molecule
Rad51, and all were found to be upregulated. But why were
we seeing so much stress in these cells?
After Thanos left The Wistar Institute, we approached Paul
Leiberman, who was studying Epstein-Barr virus, DNA replication, and telomeres. He had a postdoctoral fellow from Thanos’s
laboratory, Andy Schneider, who agreed to help along with
Paul, and we spent a lot of time talking about what might be
going on. First, to further confirm that there was actually
DNA damage, we performed a comet assay in which cell lysates
were electrophoresed in a gel. Different-sized DNA strands
move toward the positively charged end of the gel at different
rates, and the level of DNA damage is determined by the size
of the tail. As seen in Figure 4C and 4D, the nonregenerative
cells showed little evidence of comets (4%), compared with
the regenerative MRL cells, which showed 85% of the cells
as comets. Such a result was consistent with a G2 arrest interpretation of the cell cycle analysis results. What exactly is
happening remains to be determined, but the differences are
striking.
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Figure 6. Similarities in cell cycle regulation between MRL cells and
axolotl cells. The MRL mouse shows a DNA damage response. p53 is upregulated, but p21 is not expressed and the cells do not arrest in G1. Instead, like axolotl cells, MRL cells arrest in G2, and both species show
upregulation of Evi5, a molecule that enforces G2 arrest by stabilizing
the antigen-presenting cell inhibitor Emi1. When cytokinesis occurs, it requires both Evi5, which is upregulated in axolotl and MRL cells, and
MKLP1, which is upregulated in MRL cells.
The level of damage and potential arrest in G2 suggested that
a G1 arrest, which might be expected, was avoided because of a
potential lack of a G1 cell cycle checkpoint. Of several G1 checkpoint genes, p15, p16, p21, and p27, the first such gene that was
examined was CDKN1a, or p21cip1/waf1. Cells from nonregenerative B6 mice, the human cell line HCT, and cells from regenerative MRL mice were examined. Western blots showed that
p21 was missing from MRL cells, with or without irradiation
(Figure 5A). The next step was to determine whether the elimination of p21 would lead to ear hole closure. A p21 knockout
mouse (B6;129S2-Cdkn1atm1Tyj/J) made by Tyler Jacks was
available from Jackson Laboratories. Cells from the p21 knockout mouse were examined for a DNA damage response (phosphorylated H2AX levels), comets, and the cell cycle pattern, and
all showed a response profile similar to that of MRL mouse cells
(Figure 5B). Next, we performed ear hole injuries. As we had
seen in the MRL mouse, ear hole closure occurred over the
same period with the same kinetics (Figure 5C and 5D) [39, 40].
The role of p21 in regenerative healing is not known. However,
the lack of p21 could lead to a lack of senescence, reduced levels
of transforming growth factor β, and reduced myofibroblast differentiation, leading to reduced scarring. It could also promote a
more dedifferentiated state [41, 42]. One interesting model
comes out of a study comparing an MRL ear hole closure to a
regenerating amphibian limb, performed with David Stocum
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[42] (Figure 6). The molecule Evi5 (ecotropic viral integration
factor 5) is upregulated during the blastema phase (the first 7
days) of regeneration, during which mitosis is low. This is
true in the axolotl amputated limb and the MRL injured ear.
Evi5, a 110-kDa protein, prevents premature entry into M
phase of the cell cycle by binding to and stabilizing Emi1
(early mitotic inhibitor 1). After mitosis and cleavage of the
molecule to a 90-kDa form, Evi5 is found in the mid zone
and is required for cytokinesis. Another molecule in MRL regenerating tissue is MKLP1 (or Kif23; a candidate regenerative
MRL gene), which is also found in the mid zone and involved in
cytokinesis. With Emi1 being central to maintaining G2 arrest,
the loss of p21 will further promote arrest since p21 has been
shown to downregulate Emi1 [43].
This might suggest what p21 is actually doing. Loss of p21
would allow the bypass of the G1 checkpoint. With DNA damage, the cells arrest in G2. This is enhanced by upregulated Evi5
stabilization of Emi1. However, with the loss of p21, Emi1 is
further protected from downregulation.
CONCLUSION
The MRL mouse has turned into a deep well of discovery, from
its metabolic state, which is aerobic glycolysis [44, 45], to a healing microenvironment similar to that seen in the tumor microenvironment [46–48] but without the development of cancer.
Furthermore, genetic mapping studies refined by polymorphic
differences have led to the identification of 34 candidate genes
on multiple chromosomes [49–54]. One of these genes, Rnf7, is
a component of E3 ligase complex, which ubiquinates HIF1a
when hydroxylated under normoxic conditions. Its low expression level in MRL mice may be responsible for the high levels of
HIF1a found in MRLs [54], which may in turn lead to enhanced
aerobic glycolysis [44].
Notes
Disclaimer. The contents are solely the responsibility of the authors
and do not necessarily represent the official views of the National Institutes
of Health (NIH).
Financial support. This work was supported by the National Institute of
Allergy and Infectious Diseases, the National Institute of General Medical Sciences, the National Institute of Dental and Cranial Research, and the National
Cancer Institute (Cancer Center Support Grant CA010815 to The Wistar
Institute), NIH; the American Cancer Society; the Harold Y. and Leila
G. Mathers Foundation; and the F. M. Kirby Foundation.
Potential conflict of interest. Author certifies no potential conflicts of
interest.
The author has submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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