Team science in type 1 diabetes: new insights from the Network for Pancreatic Organ Donors with Diabetes (nPOD)
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CellR4 2016; 4 (5): e2128
Team science in type 1 diabetes: new insights from the
Network for Pancreatic Organ Donors with Diabetes (nPOD)
G. Lanzoni1-3, M. Pokrywczynska2-4, L. Inverardi1-3
1
Diabetes Research Institute, University of Miami, Miami, FL, USA
2
The Diabetes Research Institute Federation
3
The Cure Alliance
4
Department of Regenerative Medicine, Nicolaus Copernicus University in Torun, Ludwik Rydygier Medical College in Bydgoszcz,
Bydgoszcz, Poland
Corresponding Author: Giacomo Lanzoni, Ph.D; email: GLanzoni@med.miami.edu
Keywords: Type 1 Diabetes, Beta cells, Autoimmunity, causes severe loss of insulin-producing beta cells
Team Science, Etiopathogenesis of Type 1 Diabetes, Beta cell in the pancreas1. While progress has been made in
biology, Islet autoimmunity. clinical trials to predict this disease2, as of today no
means exist for effectively and fully preventing or
A bstract reversing T1D3. This is largely because the cause
Type 1 Diabetes (T1D) is a chronic autoimmune of T1D is still unknown4. Many traits of the patho-
disease leading to severe loss of insulin-produc- genesis and disease progression remain obscure
ing beta cells in the pancreas. The causes of this (see Box 1 ‘Studying the pathogenesis of T1D’).
disease are still unknown. Due to this fact, T1D The JDRF Network for Pancreatic Organ Donors
cannot be effectively prevented or reversed. Pan- with Diabetes (nPOD), a tissue bank and a collab-
creas or islet transplantation can revert diabetes, orative project, launched in 2007 to advance the
but require chronic immunosuppression, and understanding of human T1D through the study of
both chronic rejection and recurrence of islet au- the pancreas and other tissues harvested from de-
toimmunity may affect long-term graft survival. ceased organ donors5. Donors recovered by nPOD
The JDRF Network for Pancreatic Organ Do- include those with T1D and those with islet auto-
nors with Diabetes (nPOD) is a tissue bank and antibodies in the absence of clinically overt T1D,
a team science effort aimed at understanding the which could provide key insight regarding the pre-
etiopathogenesis of T1D. nPOD has enabled un- diabetes phase. Moreover, nPOD has recovered
precedented access to rare tissues derived from donors with monogenic forms of diabetes, as well
organ donors with T1D and with risk for the dis- as donors with Type 2 Diabetes (T2D), and those
ease to investigators worldwide. The 8th nPOD without diabetes6. Since its inception, nPOD has
Annual Meeting revealed new insights on T1D, built a sizable collection of donor specimens and
covering multiple aspects of etiology, beta cell bi- has supported a large number of studies led by in-
ology, and islet autoimmunity, emerging from the vestigators worldwide7. Investigators with an inter-
studies of nPOD investigators and collaborative est in T1D and in team science can join the nPOD
working groups. The data being generated and research community, and can find detailed descrip-
shared by nPOD investigators will be instrumen- tions of the numerous nPOD projects on the web-
tal in translating findings into better therapies, site www.jdrfnpod.org. Moreover, nPOD is com-
possibly even a cure or prevention, for T1D. mitted to promoting collaboration and team science
by creating a network of nPOD investigators with
an interest in the pathogenesis of human T1D who
nPOD: Team science in collaborate on the study of pancreata from organ
the field of Type 1 Diabetes donors. Thus, nPOD is a tissue repository, a net-
Type 1 Diabetes (T1D) is a human disease char- work of investigators and a data sharing platform
acterized by an autoreactive immune attack that – but most of all, it is the largest and most active
12 G. Lanzoni, M. Pokrywczynska, L. Inverardi
team science community in the field of T1D re-
search. Besides regular interactions via electronic tissue bank and Pathology core provide a we-
and telecommunication means, nPOD investiga- alth of information for each case6. All working
tors come together for a face to face meeting on an groups are committed to sharing methods and
annual basis. The 8th Annual nPOD Meeting was results. Here we list a series of putative ‘stages’
held in Miami, USA, on February 21-24, 2016. The of disease, following a staging system proposed
meeting was attended by over 260 scientists from by George Eisenbarth4, and we indicate how the
all over the world. The scientific program included work of nPOD groups could fill the gaps.
25 sessions with lectures by top experts in the field,
oral abstract presentations, poster presentations, Stage 1: GENES. Over 50 risk gene variants
discussions and working group meetings. Many for T1D have been identified8,9, representing
important aspects of T1D were discussed – includ- Stage 1 of the progression toward T1D. T1D
ing etiology, immunology, autoimmunity, beta cell could be considered a polygenic disease with
biology and regeneration. In this report we pres- incomplete penetrance. The most important
ent highlights of the findings reported at the 2016 genes conferring risk are certain variants of
nPOD meeting, grouped by areas of interest. the HLA Class II (primarily certain risk alleles
in the HLA-DR and HLA-DQ loci) and HLA
Class I genes, followed by a series of genes in-
BOX 1. Studying the pathogenesis of T1D volved in immunity and beta cell function. A
group of nPOD investigators (nPOD Omics
The goal of nPOD is to advance the under- working group) is generating and analyzing
standing of human T1D occurrence through data from nPOD samples that address genetic
the study of the pancreas and other tissues from factors with genomics, gene expression, and
organ donors. The pathogenic events that lead epigenetic approaches. Moreover, there are
to T1D remain obscure and represent the main also coordinated efforts involving proteomic
focus of the nPOD community. When studying approaches. These studies have the potential
the disease pathogenesis it is important to take to determine how the genetic and molecular
into consideration that the disease is chronic bases of the disease facilitate disease progres-
and evolves over a long period of time. Cer- sion. These studies could also enable detection
tain organ donors might have been developing of somatic mutations and other characteristics
T1D and the study of their organs may provi- that could be associated with more aggressive
de information about early stages of the dise- forms of the disease.
ase pathogenesis and, possibly, key etiological
factors. Donors who have recently developed Stage 2: TRIGGER. One or more envi-
clinical T1D are traditionally thought to be ronmental triggers are believed to exist and are
more likely to show pathological signs of ac- proposed to act during Stage 2 of the progres-
tive disease and to maintain a significant beta sion towards T1D4. The ongoing global incre-
cell mass. However, data emerging from nPOD ase in T1D incidence3 cannot be explained by
and other studies show that both autoimmunity genetics alone, and it is thought to be connected
and beta cell mass continue to be detected for to environmental triggers that promote disease
several years after onset. In addition, T1D may development. Enteroviruses have long be su-
also develop in pancreas transplant recipients, spected to play a key role in T1D but systematic
in which case the condition is termed “T1D re- studies of these and other viruses have not been
currence”. nPOD is making efforts to recover possible in the absence of donor specimens.
pancreata from organ donors in all of the above With the availability of nPOD samples, the
categories6. nPOD encourages collaborations nPOD-Virus working group has been formed
among investigators and has implemented a to specifically investigate the role of viruses
data sharing platform (DataShare) to maximi- in T1D pathogenesis. This group is examining
ze the potential of the data obtained from these pancreas and other tissues from organ donors
precious tissues by the community. The nPOD with T1D using a variety of methodological ap-Team science in T1D: new insights from nPOD 3
proaches to generate robust data about the pre- recent studies from both experimental models
valence of viral infections in the pancreas with and nPOD specimens illustrate the importan-
T1D and their features. Hopefully, this effort ce of extracellular matrix components in the
will lead to the identification of the most preva- evolution of the insulitis lesion. Some of these
lent viruses and will generate information that components are critical to islet structural in-
is critical to the development of viral vaccines tegrity and beta cell function, and others are
and/or anti-viral therapies. important for the trafficking of immune cells
to the islets. An nPOD working group is fo-
Stage 3: BETA CELL AUTOIMMUNI- cused on the involvement of islet and lymph
TY. In most patients, autoantibodies targeting node extra-cellular matrix components in the
islet cells appear in peripheral blood10 long be- pathogenesis of T1D (nPOD-Matrix).
fore the clinical onset of diabetes, representing
Stage 3 of the progression toward T1D4. These Stage 4: BETA CELL DYSFUNCTION
autoantibodies are believed to mark the acti- AND LOSS. Beta cells become progressively
vation of the autoimmune process. The risk impaired in the period that precedes the clinical
of disease increases when the number of au- onset of T1D. The decline in beta cell function
toantibodies increases1, 10. The beta cell mass is evidenced by loss of first-phase insulin re-
seems to be normal, if not slightly increased, sponse to an intravenous glucose challenge and
when one or two anti-islet autoantibodies are later by the appearance of impaired glycemic
present in the blood11. Insulitis is the patho- regulation14. Severe beta cell dysfunction and
gnomonic inflammatory lesion affecting the loss become apparent during Stage 4 of the pro-
pancreatic islets in T1D. It consists of a lym- gression towards T1D4. It is emerging, however,
phocytic infiltration of islets12 even though it that the extent of beta cell loss is typically less
appears to affect only a modest percentage of than previously thought in many patients. This
islets at any given time11. Insulitis and beta cell highlights the importance of dysfunction of the
loss progress with a “lobular pattern”, i.e. a di- residual beta cells as a factor in the development
screte distribution in the pancreas4. The lesion of hyperglycemia and diabetes symptoms at the
consists of inflammatory cells, mostly T lym- time of diagnosis and possibly beyond15. A se-
phocytes, and studies of nPOD samples have ries of pilot experiments by nPOD investigators
shown the lesion to contain populations of au- is testing the feasibility of generating pancreas
toreactive T lymphocytes reacting against islet slices to assess beta cell function from nPOD
cell autoantigens13. The nPOD-Autoimmuni- organ donors, without the confounding factors
ty working group was launched to study the associated with islet isolation procedures. Islet
features of the autoimmune responses through function is also assessed in isolated islets when
the study of the nPOD pancreas and lymphoid isolation can be performed.
tissues (spleen, pancreatic lymph nodes), in-
cluding the antigen specificity, phenotypic Stage 5: CLINICAL ONSET OF T1D.
features and the T cell receptor repertoire of Clinical onset of T1D, presenting characteristic
autoreactive T cells. The group also examines signs and symptoms deriving from frank hy-
the role of antigen-presenting cells, including perglycemia, is thought to occur when approxi-
B lymphocytes, in the disease pathogenesis mately two-thirds of the islets have become
and is focused on revealing the mechanisms insulin deficient16. Immediately after diagnosis,
that cause an immune attack against islet cell life-saving intervention with exogenous insu-
autoantigens and on the formation of modified lin therapy is started. Cases of death at onset
forms of autoantigens. In addition, nPOD has are extremely rare nowadays, thanks to insulin
shown the feasibility of isolating islets from treatment. nPOD has collected a large number
donors with T1D even several years after dia- of cases post onset of T1D, and a few have been
gnosis, and investigators in this group are recovered from the time of diagnosis or very
examining islet-infiltrating T cells. Moreover, close in time to it.4 G. Lanzoni, M. Pokrywczynska, L. Inverardi
identification of Vitamin D binding protein (VDBP)
Stage 6: PERSISTENCE AND RECUR- as a novel autoantigen in T1D19. Interestingly, VDBP
RENCE OF AUTOIMMUNITY. T1D is a is expressed in pancreatic islet α cells. Anti-VDBP au-
chronic disease. Minimal function and turn- toantibodies could serve as an additional biomarker of
over of beta cells can be detected several de- T1D. Molecular pathways related to Vitamin D, which
cades after onset17, and autoimmunity persists, show a genetic association with T1D20, are once again
as well. Perhaps T1D may be considered a in the spotlight. Dr. Linda Yip (Garrison Fathman`s
chronic relapsing and remitting autoimmune Lab, Stanford University, USA) reported the findings
disease, with flare-ups of autoimmune attacks of gene expression studies in human pancreas and
counterbalanced (to an insufficient extent) by peripheral blood mononuclear cells (PBMCs) during
repair and regeneration processes. Pancreas the progression towards T1D. The group built on the
transplantation or pancreatic islet transplanta- success of previous expression studies that led to the
tion are therapeutic options for patients who implication of splicing variants of Adora1 and Deaf1
have developed kidney failure or have extreme in disease progression21. Dr. Yip and colleagues used
difficulties in managing their diabetes. Recent microarrays to study the gene expression profiles of
studies show that in both pancreas and islet pancreatic tissues (obtained from nPOD) and of pe-
transplant recipients, autoimmunity can persist ripheral blood mononuclear cells (PBMCs, obtained
and at some point become reactivated, even- via the Type 1 Diabetes TrialNet https://www.diabet-
tually leading to T1D recurrence. In pancreas estrialnet.org). The analysis was performed in tissues
transplant recipients, it is well documented from controls, nondiabetic autoantibody positive and
that this may occur despite chronic treatment T1D donors. The analysis provided a series of potential
with immunosuppressive medication to pre- biomarkers of disease risk and progression. Overall,
vent rejection18. nPOD has recovered pancreas the gene expression profiles in pancreas and PBMCs
transplant biopsy specimens from patients who have different patterns throughout the disease stages.
have experienced T1D recurrence, and studies Dr. Ivan Gerling (University of Tennessee, USA) an-
from nPOD investigators have shown patholo- alyzed gene expression profiles of islets obtained via
gical abnormalities that are largely overlapping laser capture microdissection. Islets were collected
to those found in spontaneous disease in the na- from donors with different stages of T1D: autoanti-
tive pancreas. The study of transplanted human body positive cases without diabetes (pre-T1D), T1D
pancreatic tissues could provide insights also cases at onset, T1D cases with long-standing disease,
into mechanisms of beta cell regeneration and and pancreas transplant biopsies with recurrent T1D.
the pathogenesis of T1D. This is the focus of the The patterns of differentially expressed genes and
nPOD-Transplantation18 working group. pathways suggest that T1D pathogenesis could result
from four interacting pathologies affecting beta cells:
mitochondrial dysfunction and oxidative stress, viral
Big data, novel biomarkers of infection, immune response, and replication/regen-
disease and therapeutic targets eration. Different combinations of these pathologies
The study of the appropriate samples with ‘omics’ and pathways may contribute to disease heterogene-
methods and the use of unbiased analytical methods ity. Gene expression datasets like those generated by
are providing novel insights for many human condi- Dr. Yip and by Dr. Gerling are useful for many in-
tions, along with novel biomarkers and therapeutic tar- vestigators in the nPOD community, and they can be
gets for T1D. The 2016 nPOD meeting opened with the integrated with other datasets – such as those from
keynote lecture delivered by Dr. Atul Butte (Univer- genomic, epigenomic or proteomic studies. The inte-
sity of California, San Francisco, USA). Dr. Butte has gration of these ‘omics’ data will allow T1D inves-
pioneered an approach for the discovery of molecular tigators to formulate new questions and obtain deep
pathways associated with disease, of biomarkers and insights from the available samples and databases.
of therapeutic targets, that is based on the analysis of These are the focuses of the nPOD-Omics working
published omics data. He presented several examples group, a collaborative group focused on high through-
of successful applications of this data mining strategy. put studies and dataset integration, which met and
For example, he presented expression-based genome- discussed strategies in a dedicated time slot during
wide association studies (eGWAS) that enabled the the meeting.Team science in T1D: new insights from nPOD 5
modified forms of self-antigens. The factors that
BOX 2. The George Eisenbarth contribute to the generation of modified self-pep-
Memorial Lecture tides could affect very different organs, but may
ultimately trigger similar responses in immune cell
nPOD has instituted a lecture to honor the late populations.
Dr. George Eisenbarth, a true pioneer in T1D Drs. John Harris (University of Massachusetts,
research who inspired and supported the crea- USA) and James Krueger (Rockefeller University,
tion of nPOD4, 22. Dr. Gerald Nepom (Benaroya USA) presented insights from other autoimmune
Research Institute at Virginia Mason, USA) diseases – respectively vitiligo, and psoriasis. Of
delivered the lecture and reviewed the use of note, Dr. Eisenbarth often paralleled the patchi-
immunological monitoring tools in the context ness of the insulitis with the distribution of vit-
of clinical trials. He highlighted the concept of iligo. Dr. Harris highlighted how cellular stress,
combinatorial, sequential pharmacological re- reactive oxygen species and abnormal activation
gimens in which islet autoimmunity is initially of the unfolded protein response contribute to the
arrested with a depleting or debulking agent, development of vitiligo and autoimmune diseases
and a sustained therapeutic benefit is achieved in general24. He is studying strategies that block the
in the long term by using immunoregulatory Interferon-gamma/CXCL10 pathway that, in skin
and/or anti-inflammatory agents. Alefacept, a cells, is responsible for the recruitment of autoreac-
promising drug that targets effector memory T tive CXCR3+ CD8+ T cells25. The same pathway
lymphocytes, has shown efficacy in a recent cli- (CXCL10/CXCR3) has also been linked to T1D,
nical trial23 and could be a good depleting agent which has sparked interest in pharmacological
with specificity for memory cells, which have strategies to block it26. Dr. Krueger was among the
been linked to T1D. Of note, findings presented first to report that psoriasis is an autoimmune dis-
at the nPOD meeting by Dr. Pugliese and his ease, which led to more effective therapies for this
team demonstrate the presence of memory T disease. Psoriasis is a chronic disease characterized
cells in the insulitis lesion. by epidermal hyperplasia resulting from keratino-
cyte proliferation in response to cytokines released
by T-cells and dendritic cells (DCs). Tofacitinib,
Immunology, autoimmunity and modified a Janus kinase (JAK) inhibitor, attenuates JAK/
self-antigens (how and why beta cells become STAT signaling in keratinocytes, reduces the num-
immunogenic?) bers of pathologic T-cells and DCs and inhibits the
The concept that T1D is a chronic autoimmune IL-23/TH17 pathway. Similar pathways may be in-
disease was crystallized by the work of Dr. George volved in T1D, and the development of therapeutic
Eisenbarth3,4,22. Dr. Eisenbarth realized that pre- approaches could benefit from cross-fertilization
vention and a cure for autoimmune T1D could be among the different fields of research in autoim-
possible but would require a clear understanding of mune diseases.
key pathogenic mechanisms of autoimmunity. The In autoimmune T1D, several outstanding ques-
nPOD-Autoimmunity group studies autoreactive tions remain in relation to how the immune system
T cells, B cells and other types of immune cells. targets beta cells, and why immune cells exist that
T cell receptor sequences, antigen specificities and could target self-antigens in beta cells. Dr. Emil
functional properties of immune cells are at the Unanue (Washington University, St Louis, USA)
center of interest for this working group. At the described a process through which the contents of
nPOD meeting there were also presentations from the beta cell secretory granules become available
experts in other autoimmune diseases, describ- to the immune system: beta cells transfer vesicles
ing groundbreaking findings and new concepts in containing insulin and its catabolites to islet phago-
the field of autoimmunity. Different autoimmune cytes for presentation to T cells27. Thus, beta cells
conditions share a similar genetic basis, immuno- appear to play an important role as source of au-
logical mechanisms, and potentially etiology – as toantigens during the development of T1D. But
suggested by simultaneous multiple autoimmune why do we find immune cells targeting beta cell
syndromic cases. A recurring theme emerged from antigens? These cells have escaped thymic selec-
several studies: autoimmunity may be triggered by tion, or perhaps the antigens that these cells have6 G. Lanzoni, M. Pokrywczynska, L. Inverardi encountered during thymic selection differ from granin A or insulin and neuropeptide Y peptides. those encountered in peripheral tissues. There is These hybrid peptides acted as very potent activa- a possibility that certain modified forms antigens tors of T-cell clones derived from non-obese dia- could be generated specifically in beta cells, pos- betic (NOD) mice and human T1D patients30. We sibly only in certain conditions such as during an don’t know yet whether transpeptidated peptides infection, stress, environmental factors or chemi- and hybrid fused peptides from beta cell proteins cal reactions. The studies in rheumatoid arthritis are the actual triggers of autoimmunity. Nonethe- presented by Dr. Garrison Fathman (Stanford less, such peptides may form specifically in islets University, USA) pointed in this direction. In this and not in the thymus; hence, T cells reactive to disease, modified antigens can develop in tissues them would not be deleted during thymic selection. as a result of chemical reactions. Citrullination, There is growing evidence that autoimmunity may i.e. the conversion of the amino acid arginine to be triggered by (and targeted to) modified forms of citrulline, is a post-translational modification caus- self-antigens. Chemical reactions, inflammation, ing protein structural changes due to increased hy- cell death, viral infection or other environmental drophobicity. Citrullination can occur during cell factors may facilitate the generation of such modi- death or inflammation, and can alter antigen epi- fied forms of self-peptides. topes, rendering them immunogenic28. In rheuma- Dr. Mia Smith and Dr. John Cambier (Univer- toid arthritis, indeed, antibodies are raised against sity of Colorado-Denver, USA) reported a series of citrullinated forms of peptides. Anti-citrullinated findings related to insulin autoimmunity and to the protein antibodies are associated with more severe type of signals that could activate immune cells. disease. Smoking and periodontal infection are two Their studies analyzed insulin-binding B cells major environmental factors that contribute to the from healthy individuals, from individuals at risk triggering of rheumatoid arthritis. Interestingly, of T1D (autoantibody positive), or those with clini- citrullinated proteins appear in cellular debris af- cally overt disease. Interestingly, B cells with high ter smoking. It is interesting to observe that anti- affinity receptors for insulin appear to be polyreac- bodies to citrullinated proteins are associated with tive, as they also bind to chromatin and lipopoly- HLA ‘shared epitope’ alleles28, strongly suggesting saccharide. In healthy individuals, insulin-binding that a particular epitope modification could form B cells are anergic. In at-risk subjects and new- complexes with certain forms of HLA, giving rise onset T1D patients there is a decrease in anergic to a structure with unique structural and binding insulin-binding B cells, supporting their activation; properties. Dr. John Kappler (Howard Hughes whereas at 1 year after diagnosis, the levels return Medical Institute, National Jewish Health, Denver, to normal. The activation of these insulin-reactive USA) presented results related to modified forms B cells could derive from very different stimuli, of insulin antigens. Dr. Kappler studied the genera- including chromatin, which is commonly released tion of super agonists for CD4+ T-cells from the after cell death in damaged or infected tissues, but proinsulin peptide in human and mouse models. also lipopolysaccharide, a molecule produced by Proinsulin fragments can undergo trans-peptida- gram-negative bacteria. tion, a protease-mediated peptide fusion, and can The role of pathogens and their interactions thus become highly immunogenic insulin-derived with innate immunity in the development of T1D peptides. These fused peptides are potent stimula- may be central during the initial steps of disease tors of CD4 T cells, more so than the native pep- development. Dr. Decio Eizirik (Universite Libre tides. Such post-translational modifications of pep- de Bruxelles, Belgium) highlighted the fact that tides may occur only in the pancreas or in lymph more than 80% of the genes with variants associat- nodes and not during thymic selection of T cells29. ed with T1D risk are expressed in pancreatic islets, Novel studies by Dr. Thomas Delong and Dr. and that many of those genes are involved in innate Kathy Haskins (University of Colorado, Denver, immunity and antiviral responses31. The data pre- USA) support this notion. The group showed that sented support the hypothesis that genetic variants beta cells could form highly immunogenic hybrid promote exaggerated innate beta cell reactivity to peptides via the fusion of fragments from two pro- viral infections which could be a critical factor in teins. They identified autoantigenic epitopes that the subsequent triggering of autoimmunity. On result from the combination of insulin and chromo- a similar note, Dr. Oskar Skog (Olle Korsgren’s
Team science in T1D: new insights from nPOD 7
group, Uppsala University, Sweden) observed the overexpresses HLA class I and ‘aberrantly’ overex-
activation of innate antiviral pathways in pancre- press HLA class II before and during the insulitic
atic biopsies obtained from living patients with invasion33,34. Dr. Sarah Richardson (University
recent-onset of T1D (DiViD study). He reported of Exeter, U.K.) presented results on the correla-
that 23 out of 84 interferon-stimulated genes were tion of HLA class I hyperexpression and selective
found to be overexpressed in inflamed islets from upregulation of Signal transducer and activator of
T1D patients with recent onset. Viral sensor genes transcription 1 (STAT1) in control and T1D donor
(IFIH1, MDA5, PKR and RIG-I) were also found beta cells. In islets from T1D patients, a beta-cell-
to be overexpressed. Interferon gamma was over- specific hyperexpression of STAT1 was observed
expressed in islets and infiltrates from new-onset in parallel with HLA-class I hyperexpression,
T1D cases. These findings indicate that innate an- both at the gene and at the protein expression lev-
tiviral pathways are active in T1D islet cells at the el. STAT1 activation is centrally involved in the
time of onset and warrant further investigation in signaling pathway activated by interferons, and
search of viral entities. Such findings could have a it leads to an antiviral state and HLA-class I up-
positive impact in preventing or delaying T1D. regulation. STAT1 hyperexpression may thus be a
Dr. Eoin McKinney (University of Cambridge, driver of HLA-class I hyperexpression in T1D beta
U.K.) reported findings related to T cell exhaustion cells. This is in line with the report by Dr. Oskar
and autoimmunity. T cell exhaustion, a process that Skog, who showed that other interferon-stimulat-
promotes viral persistence and is associated with a ed and viral sensor genes were overexpressed in
poor outcome in viral infections, is associated to inflamed islets from recent-onset T1D patients.
better outcomes in autoimmunity. A low relapse Furthermore, he indicated that interferon gamma
rate was observed in multiple autoimmune condi- was overexpressed in islets and infiltrates from
tions in the presence of a transcriptional signature new-onset T1D cases, and this could contribute to
indicating CD8+ T cell exhaustion, a signature in- the observed expression pattern. Dr. Peter Butler
versely linked with a CD4+ T cell co-stimulation (University of California Los Angeles, USA) high-
signature32. lighted the need to remove the inflammation (the
Dr. Florence Anquetil (Matthias Von Herrath `fire`) before stimulating beta cell regeneration. Dr.
lab, La Jolla Institute for Allergy and Immunology, Butler addressed the role of mitochondrial damage
USA) reported preliminary but intriguing findings in T1D pathogenesis. Oxidative stress in beta cells
on the immunoregulatory molecule Indoleamine induces mitochondrial fragmentation, activation of
2,3-dioxygenase 1 (IDO1) and interleukin-6 (IL-6) apoptosis and beta cell loss. Therefore, the more
– molecules that are expressed at different levels beta cells enter the cell cycle under stressed and
in islets of autoantibody positive cases without dia- inflamed conditions, the greater could be the loss of
betes, T1D and T2D cases. IDO1 was found to be beta cells. The islet extracellular matrix represents
expressed in beta cells and was almost completely a barrier to inflammatory cells and a substrate for
absent in pancreata from T1D patients. IL-6 ap- the trafficking of immune cells. Dr. Eva Korpos
peared to be expressed at lower levels in islets from (Lydia Sorokin`s lab, University of Muenster, Ger-
double antibody positive donors compared to con- many) showed that the peri-islet basement mem-
trols, and at higher levels in T2D islets compared brane and interstitial matrix components are lost
to controls. These findings suggest a relationship at sites of leukocyte infiltration into the islet; this
between these immune mediators, T1D and T2D. was observed both in nPOD donors with T1D and
in pancreas transplant biopsies from patients with
Inflammation, innate immunity, and the gut recurrent T1D35.
Inflammation and innate immunity seem to Macrophages are among the first cell types to
characterize early phases of the disease. In indi- infiltrate the pancreatic islets during the disease
viduals at high risk for T1D and after T1D onset, process in NOD mice and BB rats. Dr. Jason Ga-
a subset of islets containing beta cells appears to glia (Joslin Diabetes Center, USA) presented results
be inflamed. An important biomarker that seems related to noninvasive imaging of macrophages to
to characterize prediabetic and diabetic beta cells, study islet inflammation. Magnetic Resonance Im-
and that disappears after beta cells loss, is HLA aging (MRI) of the clinically approved magnetic
overexpression. A fraction of pre-T1D beta cells nanoparticle ferumoxytol enables imaging of mac-8 G. Lanzoni, M. Pokrywczynska, L. Inverardi
rophages taking up nanoparticles in inflamed pan- Studies of isolated T1D islets
creatic lesions. Via this imaging method, he demon- Dr. Clayton Mathews (University of Florida,
strated increased accumulation of the nanoparticles USA) reported the key findings of an nPOD pilot
in regions of the diseased pancreas compared to con- project focused on live islets from T1D cadaveric
trol tissue, as observed in mouse models of T1D and donors. Pancreata from 3 young T1D donors (di-
in a pilot human study in T1D patients with recent sease duration up to 7 years) were recovered and
onset disease36. Other cell populations of the innate processed for islet isolation at the University of
immunity seem to play a role in early phases of T1D. Pittsburgh and the Diabetes Research Institute-
Dr. Manuela Battaglia (IRCCS San Raffaele Sci- University of Miami. Islets were recovered and di-
entific Institute, Italy) reported a series of findings stributed for analysis to several laboratories, and a
related to neutrophils. These cells are reduced in the fraction of the islets had residual beta cells. Gluco-
peripheral blood of T1D patients at onset. Moreover, se-stimulated insulin release showed that T1D beta
neutrophil counts seem to have an indirect correla- cells have a major loss of first-phase insulin rele-
tion with the risk of developing T1D: the lower the ase, which resembles observations in individuals
neutrophil count, the higher the risk in autoantibody at high risk of T1D and at clinical onset14. Moreo-
positive individuals37. Margination of neutrophils – ver, islets displayed a striking bioenergetic failure,
i.e. the accumulation of neutrophils in the periphery with defects in mitochondrial function and oxygen
of blood vessels due to adhesion to endothelial cells consumption rate. The islets showed a very high
– can be observed in the pancreas of at risk subjects. glycolytic rate. Hence, beta cells from T1D patients
Neutrophils accumulate in T1D nPOD pancreata, seem to have a major metabolic defect. Additional
suggesting that low neutrophil counts in circula- studies are ongoing, including gene expression stu-
tion are due to recruitment to the pancreas. Neutro- dies in sorted live islet cells, and studies of T cell
phil Extracellular Traps are also observed in larger receptors from islet- infiltrating T cells. Studies of
amounts in pancreata from first degree relative and live pancreatic cells and tissues should provide cri-
T1D cases, compared to controls. tical information for the development of therapies
The pancreas may not be the only organ where and curative strategies for T1D.
inflammation occurs during T1D pathogenesis.
Dr. Shannon Wallet (University of Florida, USA) Stem cells, progenitors
highlighted that the gastrointestinal tract is chroni- and beta cell regeneration
cally inflamed in T1D. Dr Wallet`s group has ob- A series of presentations focused on intriguing
served that intestinal epithelial cells have a central observations related to stem cells, progenitors and
role in the innate immune dysfunction that charac- beta cell regeneration. Beta cell turnover can be
terizes the T1D intestine. Altered innate immune detected several decades after T1D onset17. This
functions could lead to dysregulated adaptive im- suggests that repair and regeneration processes
munity. Dr. Christina Graves (Shannon Wallet’s occur in the diseased pancreas, but they are in-
group, University of Florida, USA) described the sufficient to counterbalance the loss of beta cells
alterations that appear in T1D intestinal epithelial resulting from autoimmunity. Autoimmunity and/
cells, including HLA class II overexpression and or loss of beta cells could actually stimulate beta
reduced goblet cell frequency. She reported an in- cell regeneration, as suggested by Dr. Ivan Ger-
creased expression of TLR5 and TLR5-responsive ling’s findings in islets from autoantibody positive
inflammatory innate immune genes (Beta Defen- non-diabetic cases. The results reported by Dr.
sin 2 and IL-17C). This was paralleled by an expan- Carol Lam (Jake Kushner’s Lab, Baylor College
sion of interferon-gamma producing intestinal im- of Medicine, USA) challenge in part this idea. Dr.
mune populations. Intestinal epithelial cells could Lam showed that islet cell proliferation, measured
thus perceive the environment in an altered way in with Ki67, was comparable in pancreata from
T1D, and they could initiate a miscommunication T1D and nondiabetic adolescents. This finding
with intestinal immune cells. Moving forward, one suggests the absence of compensatory beta cell
of the key aims will be to determine whether such proliferation, at least after T1D onset. The same
alterations in intestinal epithelial cells and intesti- studies identified a highly proliferative population
nal innate immunity are a cause or a consequence of α-like cells, expressing little to no glucagon and
of T1D. displaying cytoplasmic SOX9 positivity.Team science in T1D: new insights from nPOD 9
Dr. Teresa Rodriguez-Calvo (Matthias von On the same topic, Dr. Susan Bonner Weir (Jo-
Herrath`s group, La Jolla Institute for Allergy and slin Diabetes Center, Boston, USA) addressed key
Immunology, USA) showed that the insulin positive aspects of postnatal changes in human pancreas
area is increased in pancreata from islet-autoanti- and islets. Postnatal development of the pancreas
body positive non-diabetic cases – cases that could and islets is striking. Islet architecture changes
represent the pre-diabetic phase in T1D – compared with age, from simple rodent-like islets in young
to controls. Interestingly, the insulin/proinsulin ra- individuals to composite islets in adults. The beta
tio was found to be inverted in autoantibody posi- cell ratio over total pancreas is maintained, but the
tive cases. Autoantibody positive cases thus seem pancreas grows from about 20 g at age 5 up to 120 g
to have more proinsulin than insulin, and larger at age 26. Entirely new lobes and further branching
areas positive for each molecule, compared to con- are expected to form beyond age 5. Hence, com-
trols. This phenomenon was observed across the pletely new islets are expected to develop in po-
head, body and tail of the pancreas, but differences stnatal life through a mechanism that is not based
were more significant in the body and tail. These on beta cell replication39. In postnatal life, different
findings bring an important piece of information: progenitors could generate endocrine cells de novo,
compared to controls, autoantibody positive pan- including pancreatic epithelial tip progenitors (as
creata may not have lower beta cell mass, at least in suggested by Dr. Powers), ductal cells40, or other
early stages before the islet destructive process has classes of progenitors41,42. The question is whether
advanced significantly. Whether this increased beta an activation of progenitors results in a compensa-
cell mass derives from hypertrophy or hyperplasia tory de novo generation of beta cells in response to
of beta cells in the pancreas will have to be deter- increased demand during the progression towards
mined. These findings also stimulate investigations T1D and after onset. Mature endocrine cells may
aimed at analyzing the function of beta cells with also act as facultative progenitors, and/or intercon-
inverted insulin/proinsulin ratio. An abundance of vert in different endocrine cells. Dr. Pedro Her-
proinsulin compared to insulin (and C-peptide) can rera (University of Geneva, Switzerland) showed
be considered a biomarker of beta cell endoplasmic that islet endocrine cells could interconvert, i.e.
reticulum dysfunction. A study on serum samples change cell identity, in response to injury. In mou-
from the participants of the TrialNet Pathway to se models engineered to have beta cells selectively
Prevention study provided results in line with those ablated, newly formed beta cells frequently deri-
presented by Dr. Rodriguez-Calvo. Proinsulin and ved from preexisting alpha cells that spontaneously
C-peptide were measured in the serum. The proin- `reprogram` to beta cells. The form of insult deter-
sulin-to-C-peptide ratio was found to be increased mines the type of the response: if alloxan is used
in antibody-positive subjects that progressed to to cause beta cell loss, about 80% of alpha cells
diabetes compared with nonprogressors38. Thus, reprogram to beta cells, whereas if streptozotocin
this ratio may have utility in predicting the onset of is used, alpha cells reprogram at low frequency.
T1D in the presymptomatic phase. His group previously reported the interconversion
Dr. Alvin Powers (Vanderbilt University, USA) of delta-to-beta cells in juvenile and alpha-to-beta
emphasized inter-individual and age differences in cells in post-puberty rodent pancreata43. The appe-
islet cell mass. He showed that the beta cell mass arance of bihormonal glucagon+/insulin+ cells in
varies by 3 to 5 times in adults, which may have im- T2D pancreata and of somatostatin+/insulin+ cells
plications for age of onset and rate of progression. in T1D pancreata suggests that interconversion oc-
This could ultimately result in different presenta- curs spontaneously also in diabetic patients.
tions of T1D. He also reported a series of changes
that occur in islet cells throughout life. The stud- Monogenic Diabetes
ies suggest that islet cell composition is dynamic Approximately 1-5% of all cases of diabetes
throughout life: relative proportions of endocrine result from single-gene mutations and are thus
cells change with age. Beta cells, in particular, in- monogenic forms of diabetes mellitus. Congeni-
crease progressively, whereas δ cells decrease. In- tal mutations in one of a set of genes controlling
terestingly, exendin 4 (a glucagon-like peptide-1 beta cell function result in beta cell dysfunction44,
agonist) was found to promote proliferation of ju- other mutations affect insulin sensitivity. Specific
venile but not adult beta cells. treatments exist for certain forms of monogenic10 G. Lanzoni, M. Pokrywczynska, L. Inverardi
diabetes, and differential diagnosis is important of the spectrum, T1D can occur in adults (Latent or
to exclude involvement of autoimmunity. These late-onset autoimmune diabetes of adults, LADA),
monogenic forms of diabetes can be identified with but it often shows a slower course of onset and it
genetic screening. has a milder presentation. Moreover, a historic and
Dr. May Sanyoura (Siri Greeley`s group, Uni- sharp rise in obesity occurred among children and
versity of Chicago, USA) reported that 4 cases with adults over recent decades, and this complicates
monogenic diabetes were identified in the nPOD differential diagnosis of T1D/T2D, especially in
tissue repository via genetic typing. All of these patients over 30 years of age (a note highlighted
were autoantibody negative and had unique histo- also by Dr. Richard Oram). The observed spec-
logical characteristics. Thus, new data are emerg- trum of presentations may derive from different di-
ing about the pathology of monogenic forms of dia- sease processes. In support of the concept of diffe-
betes through the study of nPOD specimens. rent disease processes, Dr. Schatz reported that the
Dr. Lina Sui (Dieter Egli`s lab, Columbia Uni- incidence of insulin autoantibodies (IAA) as a first
versity, USA) presented the development of models autoantibody declines with age, whereas that of
of beta cell dysfunction via generation of induced Glutamic acid decarboxylase antibodies (GADA)
Pluripotent Stem Cells (iPSC) from patients with increases with age. Moreover, anti-CD20 (Rituxi-
monogenic diabetes. iPSC-derived beta cells reflect mab) treatment showed a positive effect only when
beta cell–autonomous phenotypes: cells from patients administered to children. Dr. Noel Morgan (Uni-
with SUR1 loss of function showed decreased insulin versity of Exeter, UK) reported findings related to
processing and increased proinsulin secretion. This different insulitic profiles and to the association of
approach enabled the creation of a platform for the different compositions of insulitic lesions with the
analysis of the effect of specific genotypes on beta level of beta-cell loss and age at T1D onset. The
cell function. The team is centrally involved in the high CD20+/CD4+ ratio in young T1D patients
development of the Helmsley Cellular Research Hub was associated with a more aggressive disease phe-
(http://www.cellhub.org) that is generating iPSC lines notype, more rapid progression and more profound
from patients with T1D, and making them available to beta cell loss45. The high CD20+/CD4+ ratio in
the scientific community. young cases could explain the responsivity to anti-
CD20 (Rituximab) treatment observed in young
Heterogeneity of T1D patients. Dr. Richard Oram (University of Exeter,
There are reasons to believe that what we call UK) presented findings resulting from the use of
`T1D` today is actually composed of a range of dif- the Type 1 diabetes genetic risk score on a cohort
ferent diseases. Compared to monogenic diabetes, of 150,000 adults. The findings indicate that T1D is
autoimmune T1D is of multifactorial etiology, and distributed evenly within the first 6 decades of life,
genetic studies indicate that variants in a large num- but after 30 years of age an increase in T2D causes
ber of genes confer increased risk. The combination mistakes in clinical diagnosis and treatment.
of the genetic variants in a specific individual will
determine not only the risk to develop T1D, but also Inspiring a new generation of T1D researchers
the pace of progression and the form of the disease. The nPOD Meeting organizers actively promo-
Recognition of this heterogeneity has implications te the participation of junior investigators and this
for diagnosis and treatment. As noted above, Dr. year planned a special session dedicated to them,
Ivan Gerling (University of Tennessee, USA), pre- which included a lecture followed by an interactive
sented results that four interacting pathologies may session. Dr. Aldo Rossini (Joslin Diabetes Center,
affect beta cells in T1D and different combinations USA), a pioneer in the field of animal models of
of these pathways may contribute to the disease he- T1D, gave a special lecture to the young investiga-
terogeneity. The issue of heterogeneity was further tors. He presented an exquisite overview of the mi-
discussed by Dr. Desmond Schatz (University of lestones in T1D research and therapy, with special
Florida, USA), who highlighted the major impact attention to open questions that still need satisfacto-
of this on disease treatment. There is a spectrum of ry explanations and to the problems that young in-
disease presentations throughout ages. When T1D vestigators are facing. Dr. Rossini and the audience
onset occurs very early in childhood, beta cell loss commented on the issues and frustrations related to
seems to progress very rapidly. At the opposite side the current research funding system, which largelyTeam science in T1D: new insights from nPOD 11
fails in supporting the youngest, most dynamic and 7. Kaddis JS, Pugliese A, Atkinson MA. A run on the bio-
creative minds. Dr. Rossini highlighted how pas- bank: what have we learned about type 1 diabetes from
the nPOD tissue repository? Curr Opin Endocrinol Dia-
sion, curiosity and gut feelings could lead to bre- betes Obes 2015; 22: 290-295.
akthroughs in research and therapy. 8. Concannon P, Rich SS, Nepom GT. Genetics of type 1A
Dr. Alberto Pugliese (University of Miami, diabetes. N Engl J Med 2009; 360: 1646-1654.
USA) and Dr. Mark Atkinson (University of Flo- 9. Todd JA. Etiology of type 1 diabetes. Immunity 2010; 32:
rida, USA), co-executive directors of nPOD, conclu- 457-467.
10. Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell
ded the meetings with remarks on the ongoing que-
antibodies in diabetes mellitus with autoimmune polyen-
stions that require collaborative efforts. nPOD has docrine deficiencies. Lancet 1974; 2: 1279-1283.
enabled unprecedented studies on very rare tissues – 11. In’t Veld P, Lievens D, De Grijse J, Ling Z, Van der
those derived from organ donors with T1D and with Auwera B, Pipeleers-Marichal M, Gorus F, Pipeleers D.
risk for the disease. Investigators from around the Screening for insulitis in adult autoantibody-positive or-
world joined their forces and launched a team scien- gan donors. Diabetes 2007; 56: 2400-2404.
12. Gepts W. Pathologic anatomy of the pancreas in juvenile
ce effort aimed at understanding the etiopathogene- diabetes mellitus. Diabetes 1965; 14: 619-633.
sis of T1D. The 8th nPOD Annual Meeting revea- 13. Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay
led new insights on human T1D, covering multiple TW, Atkinson MA, Roep BO, von Herrath MG. Demon-
aspects of beta cell biology and islet autoimmunity. stration of islet-autoreactive CD8 T cells in insulitic le-
We believe that the data being generated and shared sions from recent onset and long-term type 1 diabetes
patients. J Exp Med 2012; 209: 51-60.
by nPOD investigators will be instrumental in tran-
14. Sosenko JM, Skyler JS, Beam CA, Krischer JP, Gre-
slating findings into better therapies, possibly even a enbaum CJ, Mahon J, Rafkin LE, Matheson D, Herold
cure or prevention, for T1D. KC, Palmer JP; Type 1 Diabetes TrialNet and Diabetes
Prevention Trial–Type 1 Study Groups. Acceleration of
Acknowledgements the loss of the first-phase insulin response during the pro-
The authors would like to thank Dr. Alberto Pugliese, Dr. gression to type 1 diabetes in diabetes prevention trial-
Mark Atkinson and Dr. Amanda Posgai for critically re- type 1 participants. Diabetes 2013; 62: 4179-4183.
viewing the paper. 15. Pugliese A. Insulitis in the pathogenesis of type 1 diabe-
tes. Pediatr Diabetes 2016; 17 Suppl 22: 31-36.
Conflict of Interests 16. Foulis AK, Liddle CN, Farquharson MA, Richmond JA,
The Authors declare that they have no conflict of interests. Weir RS. The histopathology of the pancreas in type 1
(insulin-dependent) diabetes mellitus: a 25-year review
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