Untitled - Roche Trasplantes

BIOPSIA DE PROTOCOLO EN EL TRASPLANTE RENAL
However, as shown from animal models or in sequential allograft indication biopsies C4d
often can precede the onset of chronic humoral rejection, but the interval between the
stages can be very variable and quite long, and it is not known whether progression is
inexorable. Therefore, prospective long term follow-up is needed for cases of subclinical,
C4d positive humoral rejection to clarify whether this is an unavoidable precursor of
chronic humoral rejection or a sign of accommodation. Since current therapy for cases
of acute humoral rejection can be related to various sever side effects more data are
needed to further support already at an early time point (subclinical C4d detection without
pathology = stage II) a specific therapeutic intervention for the prevention of chronic
humoral rejection.
ACCOMMODATION AND HUMORAL REJECTION
Accommodation is defined as the resistance of an allograft to the acute pathological effects
of allograft-specific antibodies and complement activation. This phenomenon was
already observed in the late eighties in recipients of an ABO-incompatible renal allograft.
Transient depletion of the circulating antibodies that are specific for the blood group antigens
at the time of transplantation allows immediate allograft survival without hyperacute
rejection. However, in 90% of the cases a rebound of the antibodies with high titers in
patient’s serum leads to humoral rejection within the first 10 days. But the remaining
showed no correlation between the occurrence of humoral rejection and antibody titers
within the next 21 days. Even if the antibody titers return to pre-transplant levels or higher,
the allografts continue to function. Findings from mice models showed that, in the absence
of T-cell help (e.g., due to an initial conditioning regime), B-cells that are exposed
to incompatible antigens on allografts differentiate into cells that can produce non-complement-fixing
antibodies, and these B cells gradually become tolerant after a prolonged
exposure.
In HLA-mismatched allografts, alloantibodies can be found in the absence of clinical graft
dysfunction, herewith fulfilling the criteria of accommodation. However, patients with circulating
HLA-specific anti-donor antibodies have a greater likelihood of later allograft loss,
indicating that, if accommodation occurs under transplant conditions, then it is either transient
or insufficient to prevent chronic humoral rejection. Long term, complete accommodation
has not been documented for MHC molecules in humans so far, and the phenomenon
might therefore be partly determined by the nature of antigen.
Several molecular pathways should be involved in accommodation. A central role is most
probably located within the allografts’ endothelium which is thought to express cytoprotective
proteins like anti-apoptotic BCL-2, BCL-X, and haem oxygenase 1 (HO-1).
Increased expression of BCL-X was found in the endothelium of renal allografts from patients
with circulating donor-specific antibodies. Furthermore, HLA-class-I-specific antibodies
increase endothelial-cell expression of BCL-2, BCL-X, and HO-1, and increase the
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