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2017 ; 127
(4
): 1375-1391
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Tissue-specific exosome biomarkers for noninvasively monitoring immunologic
rejection of transplanted tissue
#MMPMID28319051
Vallabhajosyula P
; Korutla L
; Habertheuer A
; Yu M
; Rostami S
; Yuan CX
; Reddy S
; Liu C
; Korutla V
; Koeberlein B
; Trofe-Clark J
; Rickels MR
; Naji A
J Clin Invest
2017[Apr]; 127
(4
): 1375-1391
PMID28319051
show ga
In transplantation, there is a critical need for noninvasive biomarker platforms
for monitoring immunologic rejection. We hypothesized that transplanted tissues
release donor-specific exosomes into recipient circulation and that the
quantitation and profiling of donor intra-exosomal cargoes may constitute a
biomarker platform for monitoring rejection. Here, we have tested this hypothesis
in a human-into-mouse xenogeneic islet transplant model and validated the concept
in clinical settings of islet and renal transplantation. In the xenogeneic model,
we quantified islet transplant exosomes in recipient blood over long-term
follow-up using anti-HLA antibody, which was detectable only in xenoislet
recipients of human islets. Transplant islet exosomes were purified using
anti-HLA antibody-conjugated beads, and their cargoes contained the islet
endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to a
marked decrease in transplant islet exosome signal along with distinct changes in
exosomal microRNA and proteomic profiles prior to appearance of hyperglycemia. In
the clinical settings of islet and renal transplantation, donor exosomes with
respective tissue specificity for islet ? cells and renal epithelial cells were
reliably characterized in recipient plasma over follow-up periods of up to 5
years. Collectively, these findings demonstrate the biomarker potential of
transplant exosome characterization for providing a noninvasive window into the
conditional state of transplant tissue.
|Animals
[MESH]
|Biomarkers/blood
[MESH]
|Diabetes Mellitus, Type 1/blood/immunology/therapy
[MESH]
|Exosomes/*metabolism
[MESH]
|Graft Rejection/*blood/immunology
[MESH]
|Humans
[MESH]
|Islets of Langerhans Transplantation
[MESH]
|Islets of Langerhans/*immunology/metabolism
[MESH]