EURURO Vol. 71 No. 4

592 692

Studies investigating factors associated with ED follow-
ing renal transplantation demonstrated that men on CsA-
based regimens were more likely to have ED . In
addition, patients treated with CsA have been shown to
develop hypertension . Tissue studies attributed this
effect not to enhanced contraction but rather to impaired
relaxation due to decreased activity of endothelial nitric
oxide and endothelial nitric oxide synthase .
Although increased rates of hypertension have been
observed in patients undergoing chronic immunosuppres-
sion with FK506, its effect on smooth muscle physiology is
less clear Improvements in blood pressure can occur
when patients are switched from CsA immunosuppression
to FK506, and tissue studies have demonstrated that FK506
treatment resulted in improved smooth muscle function
In addition, FK506 and structurally similar
immunophillins have been shown to have neuroprotective
and neurotrophic effects . Taken together, these data
suggest that FK506 and associated compounds would serve
as an optimal penile transplant drug regimen.
A small number of studies have described animal models
of penile transplantation . Nearly all have used rats,
although one reports a canine model. None of the rat models
used orthotopic transplantation or urinary diversion via the
transplanted graft. In all rodent models, the corpus
cavernosa were not reanastomosed, and either a unilateral
dorsal artery or a corpus spongiosum arterial anastomosis
was performed. Thus, evaluation of erectile physiology in
these models is not feasible. One study using dogs performed
orthotopic penile transplantation between half-brother
beagles with negative lymphocyte toxicity tests. Erectile
function was not tested in this model. Given the inability to
meaningfully assess erectile function in the rodent model
and the impracticality and costs of using large-animal
models, we developed a reproduciblemodel of human penile
transplantation to investigate erectile physiology.
This study has limitations. The cavernous tissues were
obtained from patients with ED undergoing penile prosthe-
sis implantation; in contrast, donors without ED will be
sought for transplantation. Consequently, our tissues might
demonstrate an exaggerated response to rejection and
immunosuppression. To mitigate variations in etiology and
severity of ED between specimens, biological replicates
came from the same tissues for each culture condition that
was compared. In addition, blood group and human
leukocyte antigen information were not available for every
patient undergoing penile prosthesis, nor was cross-
matching performed between donor and recipient in this
model. Nevertheless, given the general immunogenicity of
nonautologous tissues and the small probability of an
identical cross-match between two unrelated persons, the
likelihood of a rejection reaction occurring between tissues
of two persons is significant enough for our model.
5. Conclusions
In summary, we reported the use of an ex vivo MLR using
human cavernous tissue to model penile transplantation
rejection to investigate the effects of PBMC activation in the
setting allogenic tissue exposure and immunosuppression
on corporal tissue morphology and physiology. In addition
to providing insight into penile tissue rejection, this model
can be used to screen current immunosuppression regi-
mens for their ability to prevent rejection and to optimize
erectile physiology. An understanding of the complex
interplay of tissues required for erectile function, transplant
rejection, and immunosuppression must be pursued to
maximize successful clinical outcomes in this new and
exciting area of vascularized composite allotransplantation.
Author contributions: Nikolai A. Sopko had full access to all the data in
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Sopko, Matsui, Lough, Bivalacqua.
Acquisition of data: Sopko, Matsui, Lough, Harris, Kates, Miller, Liu,
Billups, Burnett.
Analysis and interpretation of data: Sopko, Matsui, Bivalacqua.
Drafting of the manuscript: Sopko, Matsui, Kates, Redett, Brandacher,
Bivalacqua.
Critical revision of the manuscript for important intellectual content: Sopko,
Matsui, Kates, Redett, Brandacher, Bivalacqua.
Statistical analysis: Sopko, Matsui, Bivalacqua.
Obtaining funding: Sopko, Bivalacqua.
Administrative, technical, or material support: Sopko, Matsui, Liu.
Supervision: Sopko, Matsui, Bivalacqua.
Other (specify): None.
Financial disclosures: Nikolai A. Sopko certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/ affiliation, grants or funding, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: Urology Care Foundation
(N.A.S., M.K., T.J.B.), Sexual Medicine Society of North America
postdoctoral fellowship (N.A.S.), National Institutes of Health (NIH)
grants K08DK090370 and R03DK101701 (T.J.B.). NIH grant S10
OD016374 (for the microscope).
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