Medical Hypotheses 117 (2018) 7–15

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Autologous white blood cell infusion for trauma, brain trauma, stroke and T
select immune dysfunction co-morbidities: A promising and timely
proposal?
⁎
Gerald Dieter Griffina, , Dominique Charronb, Reem Al-Daccakb
a
School of Pharmacy & Health Sciences, University of the Pacific, Stockton, California, 123 Forest Ave, Pacific Grove, CA 93950, USA
b
University Paris Diterot, Paris 7, Chef de Service, Laboratory of Immunology & Histocompatibility, Hospital Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris Cedex
10, France

A R T I C LE I N FO A B S T R A C T

Keywords: All traumas suppress the immune system, resulting in higher morbidity and mortality. Infections, poor nu-
Trauma tritional status, chronic illness, fatigue, therapies or procedures performed during and after transport also
Brain trauma negatively affect the immune system. Large populations are impacted by trauma worldwide and suffer en-
Stroke ormous costs in both direct and indirect expenditures from physical, psychological and functional losses.
Immune suppression
Most therapies and studies of trauma, brain trauma, stroke, immune suppression and their co-morbidities do
Autologous wbc infusion
not address nor discuss methods that promote immune system resuscitation or efficacy to support its role in
Trauma and infection naïve wbcs
Adoptive immune therapy post-trauma healing and rehabilitation. These omissions present an opportunity for using autologous stored
naïve (unexposed to the current trauma and co-morbidities) white blood cell infusions (autologous white
blood cell infusion) (AWBCI) to supplement treatment of most traumas, trauma-associated infections, other
co-morbidities and immune suppression derived problems in order to improve the global standard of trauma
care. We hypothesize to give the traumatized patients back their own immune system that has been ‘stored’ in
some fashion, either cryogenically or just after or during the trauma event [surgery, etc for example]. We
emphasize that other treatments should not be replaced – rather we suggest AWBCI as concurrent therapy. We
present focused select animal and human studies as proofs of concept to arrive at and support our therapeutic
suggestion and hypotheses, flowing historically from donor white blood cell therapy [DLI] to close cohort
white blood cell therapy to autologous white blood cell infusion [AWBCI]. We integrate the concept of
personalized medicine from an evidence-based framework while maintaining scientific rigor and statistical
proof as a basis of our hypotheses.

Introduction
Several recently published studies further enabled our proposal and
to invite robust clinical investigation towards validation and im-
plementation of this promising therapeutic modality. We aim to in-
crease the standard of care for the populations suffering from a variety
of traumas and immune suppressions, and to propose a potential
therapy to ease the suffering of all trauma immune suppressed patients
globally. It is important to note that we propose new white blood cell
science therapy and not stem cell therapy.
Traumas, traumatic brain injuries and strokes are accompanied by
immune suppression, poor healing, prolonged recovery, infections
etc, and represent major health care problems and a significant global
health care challenge [1]. It is estimated that many engaged in active
combat for several months or more in Iraq/Afghanistan or potentially
other conflicts [ie-Syria, Yemen, Somalia, Ukraine, etc] are at risk of
developing disabling disorders resulting from blast waves caused by
improvised explosive devices (IEDs), rockets and mortar attacks in
addition to open or closed head trauma from shrapnel, artillery,
bombs, blunt head trauma, accidents [2,3] or multiple other bodily
injuries. The average ‘dirty’ wound from an IED or bomb explosion
requires many surgeries and intensive care. At least ∼30,000+ or
more such surgeries have been performed [4] on western coalition
trauma victims. These surgeries are also immune suppressive while

⁎
Corresponding author.
E-mail address: k6md@aol.com (G.D. Griffin).

https://doi.org/10.1016/j.mehy.2018.05.012
Received 9 March 2018; Accepted 14 May 2018
0306-9877/ © 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
G.D. Griffin et al.
potentially limb or life-saving. Data from the forces fighting against
NATO/Coalition and western world forces or internal fighters are not
available, but we must infer that the same numbers of traumas and
immune-suppressive sequelae are also present in those soldiers as
well as civilian war and terror attack victims. First responders, health
workers and rescuers, police and athletes around the world add to the
number of individuals of the trauma induced immune suppressed
populations. The traumatized populations with immune suppressed
derived and co-morbid illnesses point to a profound global issue with
enormous health and cost impacts. The global trauma load and its
induced immune suppression with multiple sequelae is therefore
ready for further studies and clinical applications such as the pro-
mising white blood cell therapeutic modality we propose. [5]. We
seek expeditious further studies for each of our presented proofs of
concept, hypothesis, notions and questions for further substantiation
leading to expeditious application and clinical use for the globally
affected trauma patient populations.
Every post-trauma care plan requires life-saving procedures, re-
suscitation, surgeries, rehabilitation as well as immune system en-
hancement for appropriate support and care. Current post-traumatic
therapy generally consists of evacuation or transport during which
many procedures and therapies are performed on the trauma victims
en-route to better healthcare. These en-route procedures and therapies
may include blood transfusions and steroids which are also both im-
mune suppressive [6], narcotic and non-narcotic pain medications,
anesthesia and additional medications and other potential immune
suppressive surgery or procedures. The life and limb-saving actions are
necessary despite their potential negative immune system sequelae and
potential failure. The immediate resuscitative trauma care phase may
be followed by potentially many surgeries and procedures lasting for
months or years.
We make a strong case for instituting rapid immune system recon-
stitution after most traumas, perhaps during the ‘transport and life/limb
saving - procedure’ events, but certainly as practical as possible in the
emergency room, operating theater or intensive care [ICU] or wards.
Healing could potentially be enhanced and recovery shortened, while
the high costs associated with critical care, nosocomial infections or
immune suppressive medications and procedures are potentially low-
ered.
Blast trauma injuries are finding their appropriate place in the
overall milieu of brain trauma. Tau type proteins in blast brain injuries
are emerging as potential markers and co-morbid factors in chronic
traumatic encephalopathy (CTE) [7–9]. The pathologies caused by blast
brain injuries are also accompanied by immune suppression, infections,
poor healing, and long-term psychological, physical and functional
deficits as with other ‘invisible’ brain injuries [10,11]. Trauma induced
immune suppression is a universal problem for all individuals engaged
in battle globally, friend or foe, whether in war, on the athletic field, on
unsafe streets or from terrorist attacks.
Historically, Donor Adoptive Immune Therapy or Donor
Lymphocyte Infusion (DLI) was advocated for cancer in the past by
Rosenberg [12], and many cases noted its success. The literature re-
flects rare attempts of autologous white blood cell re-infusion for
some human patients with cancers with no conclusive or positive
results [13,14]. However, DLI wbcs may require heavy medication
use that induces further immune suppression to treat a potential HVG
[Host Versus Graft] reaction. We ask at what point can close cohort
wbc DLI provide the same results or function as autologous wbc re-
infusion? How close a donor match is visible by the recipient’s
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Medical Hypotheses 117 (2018) 7–15
immune system as close cohort? As clinicians, we are told “match or
no match”. Where are the genetic ‘break points’ indicating ‘close
cohort’ or ‘match’ for better decision making? In some cases, donor
bone marrow is transplanted, and upon the re-infusion to the donor
may be considered ‘autologous’. Some genetically engineered, ex-
perimental models or chemically treated wbcs may also be considered
‘autologous’ as a special case. These questions seek experimental
clarity and study.
Further questions concern the time line of when the wbcs lose
trauma or infectious naivety when they are epigenetically changed to
reflect a trauma or infection response. Is there a time period before
this effect is noted in the wbcs, and how rapid or when? If studies
reveal a time period before the current trauma or infection ‘naivety’
is lost or the epigenetic trauma changes become overwhelming, then
perhaps the trauma victim’s wbcs can be drawn as soon as possible
after the trauma occurs, but before epigenetic changes occur, and re-
infused when or before the immune system becomes dysfunctional. A
follow-on question is to ask how long does the ‘naivety’ loss last?
Forever? Or how many series of cell cycles/apoptosis cycles does loss
of naivety last assuming the trauma ceases? Can the epigenetic loss of
wbc trauma naivety be overcome by multiple serial doses of trauma
naïve wbcs? If the trauma has stopped, will eventually the damaged
wbcs and their effect disappear, aided by dilution, apoptosis etc and
as we believe by a ‘new’ and younger infused immune system? These
questions seek serious study and resolution. A Graft vs Host reaction
(GVH or HVG) can be a frequent serious adverse reaction with DLI or
stem cell transplants that results in a strong immune rejection re-
sponse and further immune suppression from the medications used to
treat the GVH. Additionally, the graft may end in failure or death.
Potential hidden infective agents and genetic mis-matches in grafts
may also cause problems. Close cohort wbc infusion may be useful for
trauma after a match from a healthy donor is found. There is no
GVH/HVG reaction with autologous wbc infusion. These comments
and questions offer fertile ground for further studies and experi-
mentation.
We consider stroke to be a traumatic brain injury (TBI) because
clinically strokes result in the same potential endpoints as other TBIs
and mTBIs [minimal traumatic brain injury]/concussions] or blast in-
juries: neuronal or other tissue loss, immune suppression, infection, and
cognitive or functional losses. This may suggest that the different
trauma induced immune responses/pathways may be along a common
molecular intracellular pathway while etiologies may differ even as
they direct similar intracellular responses [GDG]. This notion deserves
study and clarification.
The immune system acts as an interface between ‘self’ and the ex-
ternal insult, be it trauma, infection or neoplasm, and is engaged and
altered while acting as a first and long-term line of defense. The failure
to restore or enhance immune system health following trauma is global
in nature and not time, nation, conflict nor trauma specific. All victims
worldwide suffer the same consequences from traumas-immune sup-
pression, infections and other sequelae. The symptoms of trauma, the
physical losses from trauma and the psychological wounds from trauma
are usually addressed and treated, but the recovery and health of the
immune system appears to be globally ignored. We have a duty to
medical science, clinical practice and our traumatized patients to im-
prove this ill addressed need and recognize the critical importance of a
healthy immune system as a part of the overall treatment plans for all
trauma patients.
This clinical translational and investigative paper is a focused
G.D. Griffin et al.
presentation of select literature relevant to immune suppression
and dysfunction secondary to trauma and select co-morbidities. We
‘connect the dots’ as a ‘thought experiment’ through investigation
of various clinical areas and research studies based on sound sci-
ence. We hypothesize that the use of autologous trauma and in-
fection naïve wbcs infused after trauma and immune suppression
regardless of the cause restore immune function, enhance healing,
potentially save lives and huge health care costs. We welcome study
and further research generated by our proposal which could po-
tentially lead to a promising new important therapeutic modality as
a welcomed next step in world-wide trauma and immune suppres-
sive care.
Immune suppression in trauma: The what, how and why of
traumatic immune suppression
Lennard and Browell described the ‘what’ of immune suppression in
[surgical] trauma [15]. They observed a post-operative or post-trauma
decrease in the number and functions T-lymphocytes, natural killer
(NK) cells, cytokines and receptors that control immune effector cells,
leaving the patient’s immune system less functional. They also noted
that specific post-operative defects in neutrophil chemotaxis, phago-
cytosis, lysosomal activity and super-oxide production in addition to an
increase in the level of prostaglandin E2, the defective secretion of
monocyte interleukin (IL-1), and the diminished production of inter-
feron gamma (IFG).
These findings reflect immune suppression and defective immune
functions after trauma. A ‘dose response effect’ was also suggested: the
longer the trauma or surgery, the longer the immune system suppres-
sion and more difficult the recovery from the trauma. Flow-cytometric
studies conducted to compare minimally invasive surgeries to open
surgeries immune status showed significantly fewer lymphocytes, in-
cluding CD3+ and CD4+ cells, along with fewer HLA-DR molecules on
open-surgery monocytes [15,16].
Strong support for a ‘how and why’ was demonstrated in studies by
Laudanski et al. [17], who analyzed cell-specific gene expressions and
pathways to document alterations in trauma related human T-cell and
monocyte pathways. They showed that an overwhelming first wave of
biochemical and molecular signals originated in the innate immune
system’s neutrophils and macrophages when they travel to the site of
injury to ingest and destroy invading pathogens, and that this includes
‘toxic’ factors and potentially damaging proteins. This initial response
is also damaging to the host’s T-lymphocytes that multiply specifically
in response to foreign invading cells during the secondary adaptive
phase. Activated protective mechanisms that lead to anergy and
apoptosis of the responding T-lymphocytes via caspase or other
pathways lessened the secondary immune response early on before it
could exert itself [17]. This complex process likely leads to the dom-
inance of the Th2 (anti-inflammatory/allergy) response over the Th1
(inflammatory) response as a result of the competitive interactions
between and from the effects of various cytokines and interleukins (IL)
produced by early responding wbcs. We suggest that alterations in the
balance of factors that lead to the Th2 dominant response may po-
tentially be restored and balanced by infusing trauma and infection
naïve autologous wbcs. The opposing roles that glucocorticoids and
catecholamines play during stress and trauma in the Th1 to Th2
transition also support the need to ‘calm down’ the chaotic trauma
immune response [18].
The expression of as many as 20% of the pool of human genes and
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Medical Hypotheses 117 (2018) 7–15
proteins that play roles in T-cell mediated immune responses may be
affected by trauma. These gene expressions are in addition to changes
in the expression of nearly 5700 genes that are associated with T-cell
functions that have been observed in cases of massive trauma [17].
The expressions of possibly 2800 genes are affected from trauma in
macrophages, with 338 genes exhibiting a minimum two-fold change
in expression. Twenty novel protein receptor sites or signaling moi-
eties were found to cause anergy or apoptosis in T-cells of patients
with massive trauma [17]. Are these epi-genetic changes/responses
along common pathways, or different for each type of trauma? We
[GDG] posit similar intracellular ‘immune’ pathways from differing
epigenetic signals, and encourage further studies to clarify this no-
tion.
Post-traumatic genetic changes appear to affect T-cells in at least
two ways, and may offer a partial answer to our above notion First,
they induce a marked increase in the expression of the components of
regulatory protein pathways that control their functions, and sec-
ondly, there is a decrease in the expression of signals that ‘turn off’ the
appropriate T-cells [17]. This model helps to explain the early shift in
T-helper cell responses (the Th1 to Th2 response shift) and the
downturn of the initial immune activation. Smrcka confirmed these
results in studies of war trauma victims and suggested that the im-
balance in the Th1-Th2 interactions resulted from an increase in the
levels of IL10, IL13, and IL4 levels which weakened the Th1 response
[19].
The processes that enable immune system function include the ac-
tivation of naïve cells and their differentiation into effector cells, the
completion of effector functions, the development of memory cells, and
the subsequent activation of the memory cells. [20].
A frequent question related to infections following trauma, closed
TBI/mTBI/[minimal traumatic brain injury]concussions/blast brain
injuries, and stroke concerns the source of the infection. The literature
provides strong support for bacterial translocation from the gut as a
potential source of bacterial infection and sepsis in immune suppressed
individuals. McFie reviewed a variety of illnesses and conditions that
make the gut barrier porous to bacterial migration in addition to actual
breakages that can result from ulceration or ischemic damage. [21].
Cellular pumps or the breakdown of tight junctional sites have also
been blamed. McFie states that a dynamic translocation cycle is a ne-
cessary physiologic event and strongly supports the notion that T-cell
depleted or athymic mice exhibit bacterial translocation from the gut to
the mesenteric lymph nodes as a result of their immune suppression.
[21].
Gatreaux et al. adoptively transferred T-cells to T-cell depleted mice
and showed that this inhibited the translocation of Escherichia coli
from the gastrointestinal tract to the mesenteric lymph nodes. [22].
Balzan et al. support that notion that bacterial translocations are a
source of sepsis during hemorrhagic shock, in nosocomial infections in
blood cultures, in surgical wounds and ascites [23].
The trauma of elective surgery without hemorrhaging or tissue da-
mage also causes immune system defects [6]. Immune suppression may
represent a partial explanation for the ineffective treatment of noso-
comial or post-surgical acquired hospital infections (HAI) because im-
mune supportive therapies are not offered in the pre- or post-op plan.
Similar situations may also occur in chronically ill or debilitated or ICU
patients. Islam et al. present a different but plausible theory of infection
in ‘sterile trauma’ from ‘DAMPS and PAMPS’ mentioned later in this
paper [73].
Additional experimental evidence that bacterial translocation
G.D. Griffin et al.
Table 1
Immunological Defects in Brain-injured Patients.
Defect Examples
T Cells Reduced number of total circulating T cells, T-helper cells, T-
suppressor cells, Natural Killer cells and IL2 receptor bearing cells.
Disproportionate high % of T-cells of the CD4+/CDw29+ (helper/
inducer)phenotype.
Reduction in the proliferative response of T-cells to mitogen
stimulation.
Decreased IFN gamma and IL2 production.
Anergy to delayed-type hypersensitivity skin testing.
Depression in lymphokine-activated killer cell cytotoxicity.
B-cells Reduction of IgG and IgM
Reduction in components of complement system
(C1q,C2,properdin).
Neutrophils Decrease in superoxide generation.
Monocytes Increased IL6 and IL10 production.
(IFN = interferon; IL = interleukin).
occurs in trauma was provided by a small and virtually ignored murine
orthopedic study by Oeztuna et al. [24]. Oeztuna et al. connected the
dots both separately and collectively between orthopedic trauma, brain
trauma, bacterial translocation and subsequent infection. They found
that traumatically induced long bone fractures increased bacterial
translocation from the gut to the mesenteric lymph nodes with in-
creased infection rates. Brain trauma alone also increased bacterial
translocation and infection. The results from this small but important
study seek expeditious confirmation in human clinical studies.
Immune suppression in trauma of the brain: stroke, TBI, mTBI and
blast brain injury
T-cell function recovery has been observed in some patients around
three (3) months after head injury [26]. This time frame may represent
potential infection danger for brain trauma immune suppressed pa-
tients. Harms et al. in their PANTHERIS trial showed a remarkable re-
duction in post-stroke human patients from an expected 41% infection
rate to 17% by the use of moxifloxacin 400 mg daily for at least seven
(7) days post-stroke [25]. We suggest that rapid immune system re-
constitution with autologous wbcs may also avoid undesirable sequelae
during this time frame. We present pertinent brain-trauma studies re-
presenting the literally hundreds of brain-trauma-immune system stu-
dies & papers found in the literature.
Mazzeo et al. showed that it was the severe brain injury and not
the use of cyclosporine that depressed activated T-lymphocytes early
after injury [27]. Wolach et al. [28] showed that early im-
munological defects in comatose patients after acute brain injury
were in the cellular arm of the immune system, although phagocytic
and humoral deficiencies were also detected. Wolach et al. also
described a decreased number of circulating T-cells, an increased
proportion of suppressor cells, a depressed mitogen-induced pro-
liferative response, and a delayed-type hypersensitive reaction. In
the phagocytic arm, the mean neutrophil f-MLP- and PMA-induced
superoxide anion release was also lowered, which reduced super-
oxide generation, whereas in the humoral arm, a significant reduc-
tion in IgG, IgG1, and IgM was reported. Some complement system
components were also lower, including C1q, C2, AP50 and prop-
erdin, resulting in a lower AP50 to properdin ratio. These immuno-
deficiencies are observed soon after trauma and brain injury and are
most prominent during the first few days after brain injury, and
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Medical Hypotheses 117 (2018) 7–15
precede infectious complications [19,28,29]. Dziedzik's findings
[29] that the immune factors in an elegant study of brain injured
human victims supportive of previous studies [18,27,28] were cat-
alogued in Table 1.
It is known that peripheral immune cells and central nervous
system (CNS) resident cells may cross-regulate one another via me-
chanisms that resemble the cross-regulatory interactions between
antigen presenting cells (APCs) and T-cells, and that neurologically
associated changes have been detected in the phenotypes of periph-
eral circulating wbcs [20,30,31,32]. Immune suppression may also be
a direct result of immune cells being chronically exposed to dys-
functional neurons for long periods of time. This provides another
plausible partial answer to the ‘what or why’ question. Clinical stu-
dies of severely brain damaged patients have shown that 65% of these
patients present with reduced lymphocyte counts on admission, and
that this was associated with significantly worse outcomes and in-
creased pulmonary infections [27].
Some auto-immune cells are necessary in the CNS for neural
maintenance and repair, possibly because they render the resident
microglial cells capable of fighting off adverse conditions. It has been
suggested that regulatory T-cells may allow some auto-immunity to
exist in healthy individuals without causing auto-immune disease
[33]. The activation of microglia causes them to function as antigen
presenting cells (APCs) and to express Major Histocompatibility
Complex (MHC) class II proteins that are associated with better out-
comes following CNS injury [34]. Other studies have suggested a role
for T-cell based vaccinations in neuro-degenerative disorders and that
CD4+ mediated neuro-protection was dependent on both resident
microglia and peripherally derived antigen presenting cells [APCs]
[35]. Perhaps one can consider AWBCI when drawn and stored early
in life as a 'vaccine' against trauma,immune, supression and its se-
quelae when they occur later in life? There appears to be a well-
controlled dialogue between the innate and follow-on cellular im-
mune systems sthat allow T-cells to provide ‘protective auto-im-
munity’ to motor neurons against CNS injury in immune suppressed
brain trauma patients [33,34,35].
The ‘other’ brain structures that form a part of the brain/CNS in-
frastructure also need a healthy immune system to heal. When a patient
suffers axonal/white matter or other brain tissue injury from trauma,
the blood vessels, dermal supportive structures, bony/skull fractures
must also heal as co-morbid injuries from usually mixed brain trauma
[5].
Das et al. [36] provide an excellent summary of some marginally
useful therapeutic approaches. They state that “most of these ap-
proaches aim at treating the secondary neuro-degeneration as a single
component”. The failed approaches discussed include the use of use of
thyrotropin release hormone (TRH), progesterone, heat shock proteins,
neurotropic factors, erythropoietin and many other factors. [37]. Anti-
inflammatory drugs including corticosteroids appear to have also failed
in brain trauma therapy. [38,39]. Brain trauma inflammation appears
to be a time-dependent event useful for inducing a dual microglial or
astroglial response ending in either lessened or increased inflammatory
neuronal damage [40].
As an example of the complexity of the multiple systems that play
roles and interact during brain trauma supportive of our discussion may
be appreciated by studying the following schematic diagram that shows
a possible nechanism for the complex interactions that occur between
the brain and systemic immunity after traumatic brain injury that may
be overcome by AWBCI:Fig. 1:
Das et al state that "the disruption of the blood-brain-barrier (BBB)
G.D. Griffin et al.
Fig. 1.
allows peripheral immune cells to infiltrate the brain. Interactions be-
tween brain and peripheral immune organs can cause either hyper-in-
flammation or immune suppression. Anti-inflammatory cytokines may
eventually support neuronal recovery [36]”. Perhaps inflammation can
be likened to homeostasis: enough may be beneficial, too much may be
bad?
Colak et al. used animal models to explore gene networks that are
partially involved in causing the effects of concussion or mTBI [41],
while Redell et al. observed changes in the expression of hippocampal
mRNAs in rats that had mTBI/concussions [42]. The results of potential
follow-up studies in humans may be useful in the future to develop gene
therapies for human mTBI/concussion patients. Hippocampal neuronal
loss was previously documented with increased levels glucocorticoids
following brain trauma [43] along with long-term cognitive losses
[18].Newer potential models of therapy may involve the use of auto-
immune system activated innate microglia, astroglia or dendritic cells
[33–35].These therapies could be supported by re-infusing autologous
trauma and infection naïve wbcs in the period following trauma when
the blood brain barrier (BBB) is open as a result of the brain trauma to
other migrating cells and larger protein molecules. Recent studies
support that different types of microglial and astroglial cells perform
varying functions in the brain, including acting as antigen presenting
cells and performing as the brain’s immune system [44,45].
Making invisible injuries ‘visible’
Trauma and traumatic brain injury (TBI), including severe and open
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Medical Hypotheses 117 (2018) 7–15
or closed mTBI/concussion, blast injuries and stroke are huge global
problems and a highly significant source of disability that imposes en-
ormous health care costs. In order to evaluate and properly treat these
injuries, the wounds must be visible and measurable in order to assess
the healing process serially as is done for stroke and other trauma. Open
brain injury and blast injury is a mixed injury with components of all
types of brain injury. Hence, while fractures, bleeds and brain tissue
deficits are relatively easily found, the more subtle injuries of mTBI/
concussion and blast brain trauma seek more examination for further
detection and therapy. In depth serial cognitive evaluations are valu-
able and may also show continuing brain injury after symptoms resolve.
Closed head brain trauma, mTBI/concussion and blast brain trauma are
special cases, requiring a higher index of suspicion and the use of some
‘newer’ methods of objective evaluation currently available.
The neuro-behavioral sequelae from brain injury may present dif-
ferently in each trauma victim, may not be apparent, or may never
appear. It is difficult to separate the overlapping symptoms caused by
PTS(D) and mTBI/concussion/blast injury with current psychological
or cognitive evaluation, again pointing to a need for a newer and higher
standard of care and evaluation.
A special magnetic resonance imaging (MRI) study using ‘diffusion
tensor imaging (DTI) showed that chronic mTBI was associated with
structural (axonal and white brain matter) changes in the brain at six
(6) months after injury in still symptomatic patients. These changes
were correlated with cognitive or intellectual deficit and behavioral
changes [46]. Lipton et al. used DTI to show that acute brain damage is
caused at the moment of concussion/brain injury and correlated these
G.D. Griffin et al.
acute changes with cognitive and behavioral changes [47]. Excellent
reviews by Shenton [48], Niogi and Mukherjee [49] lend strong and
elegant support for the use of DTI in mTBI/concussion. Proving that
actual injury to the white matter or axonal tracts of the brain is present
and/or resolving as symptoms resolve is basic to any standard of
medical care along with serial immune system component studies. By
using DTI to show presence or absence of concussive damage to axonal
tracts and other brain areas one can conceivably separate the post-
concussive symptoms from PTS(D) and select appropriate treatment.
Hayes et al. discuss the physics and theory of DTI [50], while also
noting that difficulty in data interpretation must be overcome. They
suggest that DTI should be the procedure of choice for war/combat
veterans suffering from mTBI/concussion or head trauma. Hayes et al.
and Militana [51] approach axonal injury from a ‘connectivity disrup-
tion’ perspective to make the mTBI/concussed brain injury more
visible. The science and physics described by Hayes is based on the
orientation of water molecules along normal, injured or inflamed ax-
onal tracts. DTI could be used in separating the symptoms of PTS(D)
from the overlapping symptoms of mTBI as noted above, and enhance
therapy for both once the true cause of symptoms is established by
serial DTI studies [50]. Militana et al. [51] also reported the use of fMRI
(functional MRI) to measure increases in cerebrovascular activity
within one (1) week after a college athletic concussion. The hundreds of
DTI supportive papers in the literature seem ignored.
A stunning paper in 2O15 by Trivedi [52] may have shown the next
step forward in the objective diagnosis of concussion/mTBI by moving
DTI science forward as has often been suggested by increased use and
showing the need and pressure for progress [5,64]. Trivedi describes
the use of 257 molecules of water in DTI instead of the usual 6 or so
molecules used. This increase on water molecules showed spectacular
‘tractography’, and one can clearly see the various tracts as they course
from one area of the brain to another, as well as damaged individual
axonal tracts. The work carried out by Schneider and Okonkwo based
on the findings by Yeh is leading the way to eventual potential FDA
approval of this advanced DTI technology, called high fiber definition
tracking [HFDT] [52]. HFDT overcomes the DTI inability to ‘see’ the
‘connectivity’ and axonal ‘mixing’ problems [50,51] with ‘normal’ DTI
studies.
Other important steps forward in our ability to diagnose newly
concussed athletes were recently reported by Kawata [53] and Lee and
Galetta [54], who found that sub-concussive repetitive head traumas
were associated with difficulties in near-point occult point of visual
convergence (NPC). These newer diagnostic procedures seek re-
producible efficacy by serial application until symptoms are gone, and
not simply to look for acute injury as a single evaluation. For example,
each of the newer mTBI procedures can be serially applied from the
moment of injury to and after symptom resolution, accompanied by
parallel immune system component studies to test the validity of the
newer methods as the immune system changes with time towards
symptom resolution and eventual brain healing. DTI or HFDT could be
used as comparison parallel standards to test the efficacy of the other
newer mTBI/concussion injury tests along with immune system com-
ponents serially. Once symptoms resolve, the utility of some of the tests
may fall off, but the continued serial and comparative study using DTI
or HFDT and immune system component levels may show the brain
healing process as axonal/white matter, hypothalamic and other da-
mage resolves. This comparative emergent serial method would bring
needed focus on the state of the white matter and axonal tract injuries
as a part of an emerging improving standard of care and could be a
measure of our proposed therapy along with serial immune factors.
Comparative and serial parallel studies mentioned above have not been
done. An acceptable standard of care should include objective proof of
brain healing and immune system reconstitution. The technology to do
so now is available, reported in many positive papers, but remains ig-
nored.
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Medical Hypotheses 117 (2018) 7–15
Of mice and men: Proofs of concept
The questions of ‘what, why and how’ of immune system response to
trauma and brain trauma discussed above lead us to further elegant
studies as proofs of concept. The proof of concept for immune system
response and co-morbid problems of brain trauma/stroke was found by
the elegant close cohort murine studies by the Prass et al. group [55].
The middle cerebral artery [MCA] induced ‘stroke immune-deficiency
syndrome’ was accompanied by bacterial infection, sepsis and the long
lasting rapid inhibition of cell-mediated immunity [55]. Prass et al.
found that the stroke-induced extensive loss of lymphocytes via apop-
tosis also caused a shift in production from Th1 to Th2 anti-in-
flammatory cytokines, supporting the results by Laudanski et al. [17].
The adoptive transfer of close cohort infection and brain trauma naïve T
and NK cells in the Prass murine model greatly decreased the total
septic bacterial burden often observed after stroke and indicates that it
is important to support and restore immune system functions in brain
trauma/stroke with infection or sepsis. A neuro-endocrine and geneti-
cally mediated systemic immune-suppression at the beta 2 receptor site
appears to be the mechanism in the development of a bacterial infection
and sepsis after trauma, brain trauma and stroke. Prass et al. also re-
ported that beta blockers ameliorated post-stroke pneumonia by finding
that interactions between catecholamines, interleukin 10 (IL10) and
interferon gamma (IFN G) were central to allowing post-stroke infec-
tions to occur. A paper among many that pointed towards the Prass
et al. study was offered by Meisel in 2005 [56], as ‘central nervous
system injury induced immune deficiency syndrome’ accompanied by
infection. A post-stroke infection model in which a dramatic reduction
in infections was achieved in human stroke patients taking and re-
maining on beta blockers while in the ICU was published by Dziedzic
et al. [57]. Chamorro et al. [58] showed that post-stroke infections are
enhanced by immune suppression with aspiration the likely direct co-
morbid cause of infection.
A work using autologous monocytes from bone marrow was re-
ported in severe brain injured children by Liao [59]. He reported that
the neuro-inflammatory induced intra-cranial pressure in pediatric pa-
tients with brain edema following severe brain trauma was reduced
after autologous monocyte infusion was shown by the lessened in-
tracranial (ICP) pressure and shortened intensive care stays required by
these patients. The infused autologous wbcs (bone marrow sourced
monocytes) may or may not have been ‘trauma and infection naïve’,
and Liao’s success speaks to our questioning of the timeline of the
trauma induced epigenetic effect on the trauma patient’s wbcs. The
patients’ wbcs may still have been trauma and infection naïve if drawn
immediately or soon after the brain trauma. This question seeks more
study and resolution. Liao’s study showed welcome health and cost-
saving benefits by shortening ICU stays and offers clinical proof of
concept seeking expeditious confirmation.
Neuro-inflammation was described by Das et al. as one of the most
detrimental co-morbidities of mTBI/concussion [36]. Savitz et al. in-
fused autologous bone marrow monocytes into 10 (ten) patients up to a
maximum dose of 10 (ten) million cells/kg between 24 and 72 h after
ischemic stroke. They reported no adverse reactions to the infusion, and
at 6 (six) months after ischemic stroke 7 (seven) of 10 (ten) patients
were doing well [60]. Villinger et al. adoptively transferred SIV-naïve
autologous CD4+ cells and induced a long-term non-SIV progressive
status in macaques [61].
A recent study by Nino et al. validated that antigen-specific T-cells
fully preserve their anti-tumor functions following cryo-preservation
and ex-vivo expansion [62]. Nino et al. showed full conservation of
differential potential of effector T-cells: the full preservation of cyto-
toxic functions, secretion of inflammatory cytokines and maintenance
of T-cell motility and their ability to infiltrate and kill tumors.
Das et al. showed that the activation of reactive microglia and as-
troglia, the opening of the blood brain barrier (BBB) by brain trauma,
the creation of reactive oxygen species, anergy, apoptosis and many
G.D. Griffin et al.
other detrimental events caused neuro-degeneration and axonal tract
damage [36] (see above Fig. 1).
These select and focused studies support the concept that re-infusing
autologous cryo-preserved or fresh wbcs and T-cells can indeed be a
plausible viable form of therapy not only for viral/SIV/AIDS infections
and immune suppression resuscitation therapy, but also for trauma
induced immune suppression, co-morbid infections and other sequelae.
We urge expeditious clinical studies for further validation.
Autologous re-infusion of pre-trauma, pre-infection cryogenically
or otherwise stored naïve, undamaged or unprogrammed immune
cells: A novel therapeutic approach
The long history of DLI successes and early AWBCI inconclusive use
in cancer treatments and infections [12,13,14,55,50,60] led to the
proposal that cancer and infection naïve cryogenically stored auto-
logous white blood cells could be infused to promote a ‘younger’ and
more effective immune system which might be a better basis for
fighting cancers and infections [63]. Perhaps obtaining these ‘younger’
naïve immune cells could and should become one goal of a global im-
munization and wbc storage effort and program? We suggest adding
‘trauma’ as a third component to earlier cancer and infection potential
therapeutic models. This visionary therapeutic program could be im-
plemented at any point from birth to just before the circulating wbcs
lose their trauma and infection naivety to become a part of a global
comprehensive health care or vaccination program.
A common thread in trauma, stroke and TBI is the Th1 to Th2 im-
mune system shift. Various complex interactions and cell signals are
structured around the Th1 to Th2 ‘switch’, and the functions they direct
in T-cells and the resultant signals are dictated by trauma activated
genes [17]. This speaks to a multiple external cellular cause but
common intracellular immune pathways but seeks further investiga-
tion. Studies have reported the presence of ‘signal proteins’ that inhibit
the immune system [54] and gene/nuclear effects that impact tran-
scription [17,37], or form cortisol complexes that mediate intra-nuclear
actions and effects. Cellular immune responses are likely further ne-
gatively impacted by a decrease in the oxygenation of damaged tissues
and a switch to anaerobic cellular respiration.
The immune system is like the traumatized patients it protects,
linked by an interdependent tumultuous and ever-changing relation-
ship. The infusion of previously preserved and trauma and infection
naïve autologous wbcs may promote a faster return to good health and
recovery for trauma/TBI/mTBI/blast injuries and stroke patients. The
microglia and astroglia in the brain could also potentially be supported
by the re-infusion of an intact and healthy immune system necessary for
maintenance or healing of traumatized neural tissues. The opening of
the BBB after brain trauma offers the opportunity for infused or other
migrating wbcs to enhance microglial and astroglial efficacy [44].
Significant health care expenditures could potentially be saved by re-
infusing a healthier, younger and intact immune system. We now know
that autologous or close cohort wbcs that were collected earlier and
stored can later be infused and are efficacious [55,60,62]. They there-
fore represent a ‘bio-resource’ that could potentially overcome pro-
blems in patients with a senescent, suppressed or traumatized and in-
fection challenged immune system including frequent impaired vaccine
responses [63,64,65]. When autologous trauma and infection naïve
stored wbcs are collected from younger and healthier patients they
contain and keep all of the necessary factors to mount a robust response
to pathogens, to neoplasms and to immune suppression from trauma
[60,62]. With AWBCI, patients do not experience the allergic reaction
from DLI membrane proteins or HLA systems as well as avoiding the
Graft vs Host reactions and rejection. The ratio of naïve re-infused
autologous wbcs to trauma and infection tainted wbcs is positively
13
Medical Hypotheses 117 (2018) 7–15
changed, and this will strongly support the patient’s immune system.
The homeostasis of naïve and memory T-cells [66,67,68] may be en-
hanced by re-infused autologous wbcs. The homeostatic energy re-
quirements of T-cells during proliferation are described by O’Sullivan
and Pearce [69] and Okoye et al [70]. in ‘thought experiments’. We
await expeditious dosing and time-line studies.
The success of DLI (wbcs) in successful anti-leukemic therapies [12]
allowed extrapolation towards potential AWBCI utility: from donor
wbcs infused to close cohort wbs infused to autologous wbcs infused
presents a logical progression of this therapy. Thus, uncompromised
autologous or possibly close cohort T-cells may represent ‘bio-resources
or potential vaccines’ that could function against future immune sup-
pression from infections [63] and trauma. It is highly plausible that
trauma cases around the world could enjoy a faster and more complete
return to prior good health with the use of this visionary protective
therapeutic modality. Fundamental to the idea of treating an immune
system that is senescent, suppressed or dysfunctional is the question of
whether the autologous or close cohort re-infusion of immune system
components that were previously collected and stored before re-infu-
sion can indeed restore immediate and robust immune functions and
promote a more rapid return to prior health. Steps supportive of the
logical progression of our ‘thought experiment’ have been provided by
Prass [55], Savitz et al. [60], Villinger [61], Liao [53],Oeztuna [24],
Islam et al. [75], and Nino [62] with elegant and solid scientific rigor,
and have enabled us to suggest this potential therapeutic modality in
answer to the above question. We suggest expeditious and robust efforts
to study and investigate these notions.
Very early proofs of concept and successes include use of adoptive
immune therapy and bone marrow transplants for victims of nuclear
disasters, radiation accidents and cytotoxic drug use some fifty (50) or
more years ago [71,72,73,74]. As mentioned, the recent superb paper
by Islam et al. [75] explores the causative action of Damage Associated
Molecular Patterns (DAMPs) and Pathogen Associated Molecular Pat-
terns (PAMPs) and potential partial reversal by of immune suppressive
mechanisms re-infusing anti-coagulated whole blood after orthopedic
surgery via ‘pathogen encoded sialidase enzymes’ [74] but seeks more
confirmation. The PAMP and DAMP explanation by Islam et al. [75] has
been advanced to replace the older SIRS and CARS explanation of
sterile infection and inflammation and awaits further resolution. The
above excellent paper and review by Islam et al. [75] supports the
works of Liao [59] and Savitz [60] since Islam’s re-infusion of anti-
coagulated whole blood from ongoing orthopedic surgery was likely
trauma naïve and also contains monocytes [59,60] and neutrophils
[77]. As said, this speaks strongly to more needed studies on the time-
line mentioned earlier in this paper for further exploration of the onset
of epi-genetic effects time lines and loss of trauma naivety. A recent
sepsis immune-suppressive paper offers refreshing answers and ther-
apeutic pathways for sepsis as well [76]. As a more recent proof of
concept, we offer a study that shows neutrophils help to heal the brain
after hemorrhagic stroke by enhancing the role of Interleukin-27 (IL-
27) in healing the hemorrhaged brain with better recovery and po-
tentially a smaller infarcted area [77]. This elegant study explores the
role of neutrophils and relationships with microglia, IL-27 and lacto-
ferrin with RBCs and the overall lessening of hemorrhage, cerebral
edema and faster resolution of the hemorrhagic stroke while also
seeking more confirmatory studies by asking pertinent unanswered
questions.
There are several critical reasons to choose a trauma patient’s own
previously drawn and stored immune cells. They have not been exposed
to the intrinsic metabolic and or degradation associated with trauma,
infection and related disease states or events, depending on time-line
studies and are therefore intrinsically healthier. Earlier stored wbcs
have also escaped the effects of substrate absence and shifts in oxidative
G.D. Griffin et al.
phosphorylation towards an anaerobic environment, and are therefore
more viable and functional. They are also ‘younger’, which assures a
greater diversity of T and B lymphocytes capable of recognizing, tar-
geting and fighting a larger number of pathogens and damaged tissues
[63]. Perhaps wbcs drawn immediately after the trauma are also still
trauma naïve, depending on more proof by timeline studies [59,60,75].
Concluding thoughts
We suggest infusing trauma and infection-naïve autologous white
blood cells (wbcs) to achieve a renewed and ‘younger’ immune system.
These wbcs could be collected at pre-trauma, pre-infection and pre-
immune suppressive time points and could conceivably be at any time
from birth to the period just before T-cell trauma and infection naivety
is lost via epigenetic pathways [17]. We show proof of concept in-
cluding post-trauma wbc harvesting, depending on time line and fur-
ther studies. The ‘set-point’ may even become a predictable target date
when white blood cells can be acquired and stored before any planned
elective ‘trauma’ or surgery including deployment. The intracellular/
nuclear immune responses also led us to the notion of potential
common immune response pathways from differing extra-cellular or
epigenetic sources. This notion helps to tie together our hypothesis and
that the differing sources of trauma are tied together by similar or
common intracellular immune pathways or responses. Again, much
food for thought and experimentation. This novel therapeutic modality
could potentially obviate short- and long-term trauma induced immune
suppression sequelae, such as poor healing in trauma-damaged tissues
(e.g., brain infrastructure, crush injuries, post-concussive syndromes,
acute and chronic infections, and PTS[D] immune suppression). We do
not nor cannot suggest not to perform immediate life-saving and stan-
dard of care maneuvers as needed. Enormous health care costs could be
prevented if a fully functional and intact immune system can be re-
stored and maintained. Additionally, shorter cost saving medication
regimens may be beneficial if we can promote the development of lesser
degrees of antibiotic resistance. The cost of drawing autologous wbcs
are similar to a complete blood count and differential (cbc & diff) draw
and study. The cost of separating out the patient's wbc is also not ex-
horbitant. The cost of storing the autologous wbcs is low-for example, a
company in southern California charges a minimal fee of ∼$150.00 per
year for cryogenic storage. These stored wbcs can be retrieved and
made ready for use easily, and can be multiplied many times with little
loss of efficacy. The cost of this visionary therapeutic modality is
minimal when one compares the costs involved versus the costs of
prolonged ICU care, prolonged healing and rehabilitation periods.
The problems associated with trauma, immune suppression and its
sequelae are global in nature, and not time, nation- or conflict-specific.
All trauma victims in all conflicts and all patients with traumas re-
sulting from other causes around the world suffer from the same pro-
blems.
Select studies relevant to immune dysfunctions resulting from
trauma are reviewed in this clinical translational investigative paper.
Supportive studies from solid and elegant science are offered as evi-
dence to ‘connect the dots’ in an effort to build a bridge with a variety of
medical subjects and clinical practices to support this novel therapeutic
approach. We believe that it is important to discover and connect po-
tential new interacting pathways across various scientific and clinical
fields. Our proposed therapeutic modality seeks expeditious translation
into many studies and useful therapy for all victims and patients who
continue to suffer from trauma globally.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at https://doi.org/10.1016/j.mehy.2018.05.012.
14
Medical Hypotheses 117 (2018) 7–15
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