H e m a t o lo g y E d u c a t io n - European Hematology Association

J.E. Hendrickson 1,2
1 Aflac Cancer Center and Blood
Disorders Service, Children’s
Healthcare of Atlanta, Division
of Pediatric Hematology/Oncology,
Emory University School of Medicine,
Atlanta, GA, USA;
2 Department of Pathology
and Laboratory Medicine, Emory
University School of Medicine,
Atlanta, GA, USA
Hematology Education:
the education program for the
annual congress of the European
Hematology Association
2011;5:366-372
Transfusion
Red blood cell alloimmunization:
of mice, men, and women
Introduction
Red blood cell (RBC) alloimmunization, or
the formation of antibodies after exposure to
non-self antigens, can be a clinically significant
problem. Sequelae of RBC alloimmunization
include timely and costly evaluations
for antibody identification and for location
of compatible blood for transfusion,
acute or delayed hemolytic transfusion reactions,
and hemolytic disease of the newborn.
1 Although some patients (“non-responders”)
fail to develop RBC alloantibodies
despite exposure to large numbers of blood
products, others (“responders”) make multiple
antibodies despite limited blood product
exposure. 2 In some instances, a “responder”
may develop so many anti-RBC alloantibodies
that compatible RBCs for transfusion
(aside from autologous RBCs) do not exist.
Outside of the very immunogenic Rh(D),
alloimmunization to other RBC antigens
occurs in approximately 3–10% of transfused
individuals, 3–6 with some patient populations
(including patients with sickle cell
disease) having alloimmunization rates up to
40–50%. 7–9 The prevalence of alloimmunization
may be even higher than previously
appreciated, as a number of anti-RBC antibodies
may disappear and then reappear at a
later date (“evanescence”). 10 The pathophysiology
of this process is not well understood,
but certain antibodies are more likely to
evanesce than others, with antibody pairs
(e.g., those developing at similar time points
after transfusion) sharing a similar evanescence
fate. Another consideration in inter-
A B S T R A C T
Red blood cell (RBC) alloimmunization can be quite problematic from a medical, as well as a logistical
viewpoint. Alloimmunized patients are at risk for hemolytic transfusion reactions, and highly
alloimmunized patients are at risk of not having compatible RBC units available for transfusion.
Although some factors influencing rates of RBC alloimmunization are obvious, others are less well
understood. Animal models have begun to bridge the gap in the understanding of both donor and
recipient factors influencing rates and degrees of RBC alloimmunization. Murine models have most
frequently been utilized secondary to their known genetic backgrounds and the number of immunologic
tools available for use. To date, four transgenic mouse models of RBC alloimmunization have
been described: the Tg-FVB model (with presumed ubiquitous expression of the human Duffy b antigen);
the mHEL model (with ubiquitous expression of membrane bound hen egg lysozyme); the HOD
model (with RBC specific expression of hen egg lysozyme, a portion of ovalbumin, and human Duffy b );
and the hGPA model (with RBC specific expression of the human glycophorin A antigen). This review
focuses on the strengths of each model system, discussing what is known and unknown about RBC
alloimmunization in mice, men, and women.
pretation of alloimmunization statistics is
that agglutination based assays utilized in
blood banks may fail to detect low levels of
anti-RBC antibodies, should they be present.
Thus, taking into account the large number
of RBC units transfused annually (>15 million
in the US alone), 11 the overall prevalence
of RBC alloimmunization is quite high.
In order for a recipient to develop an anti-
RBC alloantibody, several conditions must
be met. First, there must be antigenic differences
between donor and recipient. Given
that there are hundreds of described RBC
antigens, 12 there are typically a large number
of antigenic differences between donor and
recipient during each RBC transfusion.
Next, the recipient must be able to recognize
and present the foreign antigen. If the antigen
in question cannot fit into the recipient’s
antigen presenting cell MHC pocket, then
the steps to initiate alloantibody formation
cannot occur. For example, it is thought that
Rh(D) can be presented by an MHC in nearly
all transfusion recipients, 13 whereas Fy a
appears to be preferentially presented by
transfusion recipients with HLA DRB1*04
(0401 or 0403) or HLA DRB1*15. 14,15 Finally, it
has been hypothesized that a danger signal 16
of sorts is necessary for an immune response
in general to occur. Additional recipient factors
that influence alloantibody formation in
humans, however, are ill-defined.
Besides recipient factors, a number of
donor and product specific factors may
potentially influence alloantibody response.
It has been proposed that length of RBC storage
may influence recipient outcomes, such
as infection, deep vein thrombosis, and gen-
| 366 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)