Transplantation of pancreatic islets represents a clinical therapeutic option to preserve
and/or restore β-cell function in patients with diabetes (1,2). The source of the
islets is the patient’s own pancreas (autologous, islet autotransplantation [IAT])
when the goal is preserving pancreatic endocrine function in pediatric and adult individuals
undergoing total pancreatectomy due to pancreatitis (3,4) or trauma (5,6). Recently,
IAT has been also proposed for enucleable benign (7) and malignant (8) pancreatic
neoplasms. Transplantation of deceased-donor (allogeneic) islets is performed for
patients with brittle type 1 diabetes and hypoglycemia unawareness as islet transplant
alone (ITA) if nonuremic and as simultaneous islet–kidney (SIK) or sequential islet
after kidney (IAK) transplantation procedures if uremic (end-stage renal disease)
requiring kidney transplantation. Allogeneic islets can be part of cluster organ transplantation
(Table 1). In recognition of the excellent metabolic control obtained after islet
transplantation even when exogenous insulin treatment is required, reimbursement has
been approved in several countries (e.g., Australia, Canada, France, Italy, Switzerland,
U.K., Sweden, and the Nordic Network). In the U.S., only IAT is currently reimbursed,
while biological licensure by the U.S. Food and Drug Administration should be imminent
after recent completion of the Clinical Islet Transplant Consortium registration trials
(www.citisletstudy.org).
TABLE 1
Indications for islet cell transplantation
Since the 1970s, islets have been embolized into the hepatic portal system by a minimally
invasive technique consisting of transhepatic cannulation of the portal vein under
ultrasound and fluoroscopy guidance followed by sealing of the tract with thrombostatic
treatment (2). Alternatively, in patients at risk for bleeding, the transplant is
performed by cannulation of a tributary of the portal vein using open surgery (minilaparotomy)
or laparoscopic approach.
An instant blood-mediated inflammatory reaction occurring after intraportal islet
infusion may activate the coagulation cascade and the endothelium of the hepatic sinusoids,
triggering adhesion of platelets and leukocytes and generation of thrombi and ischemia,
contributing to the loss of a conspicuous mass of transplanted tissue. Nonspecific
inflammation generated at the time of transplant may heighten the intensity of subsequent
adaptive immune responses. In organ transplantation, these responses are responsible
for higher incidence of acute and chronic rejection episodes, and in type 1 diabetes
they also promote the recurrence of autoimmunity. Other disadvantages of the hepatic
site include the relatively hyperglycemic environment and the elevated concentration
of immunosuppressants (first-pass) that are toxic to islets.
Definition of extrahepatic transplantation sites is recognized as a research priority.
Ongoing investigations (Table 2) aimed at identifying a microenvironment that could
provide prompt engraftment and minimize early inflammation and islet cell death while
achieving sustained function are of particular interest. Engraftment of islet grafts
in several extrahepatic sites with or without bioengineering strategies has been demonstrated
in experimental models (2,9–11), although clinical translation for some remains arguable
(Table 2). An ideal new “home” for islet grafts should accommodate relatively large
volumes of tissue (e.g., low purity, or pooled donor islet preparations, and/or retransplantation),
rely on minimally invasive transplant procedures, and allow for noninvasive longitudinal
monitoring and easy access for biopsy. Portal blood drainage may be preferable to
reproduce physiological metabolic responses. Confinement and retrievability of the
graft is desirable, particularly for bioengineering approaches to optimize the site.
Extrahepatic sites already tested in humans include muscle (12,13) and peritoneal
cavity (to accommodate large microencapsulated islets) (14,15).
TABLE 2
Implantation sites for islet cell transplantation
The new pilot study by Maffi et al. (16) in this issue supports the clinical feasibility
and safety of intra-bone marrow (BM) islet transplantation. Four patients underwent
total pancreatectomy and, as intrahepatic islet transplantation was contraindicated
for anatomical or medical reasons, the autologous islet suspension (IAT) was injected
via puncture of the iliac crest under local anesthesia (Fig. 1). Neither adverse events
related to the transplant nor apparent alterations of hematopoiesis were observed.
Successful intramarrow islet engraftment was documented in all patients as detectable
fasting and simulated circulating C-peptide levels. Marrow biopsy and aspirate demonstrated
physiologic microenvironment patterns. Well-preserved islet morphology, cytoarchitecture
with normal distribution of endocrine cell subsets and vascular structures, and expression
of transcription factors specific for endocrine precursors and mature β-cells were
detected in collected specimens. Hypointense magnetic resonance imaging signal and
calcifications detected at the transplant site possibly reflect microenvironment reactivity
and remodeling worthy of further investigation.
FIG. 1.
Schematics of intra-BM islet transplantation and graft microenvironment.
The advantages emerging from this study of the marrow over the liver are easy graft
implantation and monitoring by obtaining adequate biopsies (unlike the case for intrahepatic
islets that are broadly dispersed in a large parenchyma). Appealing features of the
marrow microenvironment include its richness in hematopoietic, mesenchymal (stromal),
and endothelial cell precursors that could contribute to tissue repair/remodeling
and, in turn, promote islet engraftment (Fig. 1). Immunomodulatory properties of BM
cell subsets might assist in reducing early inflammation and improving the survival
of allogeneic islet grafts in patients with type 1 diabetes (17–19). In previous rodent
studies, engraftment and function of syngeneic islets had superior results in the
femoral BM than in the liver (20). However, in the present clinical study, C-peptide
levels appeared lower for intra-BM grafts than for comparable patients receiving intrahepatic
IAT (16). Species differences may account for the discrepancy in outcomes between
rodent and human transplants. Also, the limited number and heterogeneity of the clinical
cases does not allow for generalizations at this stage.
The pilot trial is innovative as proof-of-concept that the BM is a viable clinical
alternative to the intrahepatic site in cases in which the latter is contraindicated.
However, application of the BM as gold standard for islet implantation is questionable
at the present time. Besides lack of portal drainage and retrievability (limitations
common to the liver), additional studies are needed to further the understanding of
the features and potential of the BM site in humans, ascertaining the optimal islet
mass needed to restore euglycemia, the possibility of infusing large islet volumes
without compromising engraftment, the impact of immunotherapy on islet engraftment
and function, and the long-term efficacy and safety of clinical intra-BM islet transplantation.
Identification of a clinically relevant new home for islet grafts will likely contribute
to achieving reproducibly successful biological replacement of β-cell function in
insulin-requiring diabetes.