# Passenger Lymphocyte Syndrome and Liver Transplantation

Authors: Maxime Audet; Fabrizio Panaro; Tullio Piardi; Ping Huang; Murat Cag; Jacques Cinqualbre; Philippe Wolf
Journal: Clinical and Developmental Immunology
 (2008)

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## Abstract

The authors reviewed the passenger lymphocyte syndrome (PLS) that has appeared after transplantation. The definition, mechanism, serological, clinical features, and treatment for PLS after solid organ transplantation, especially liver transplantation, are described. The PLS refers to the clinical phenomenon of alloimmune hemolysis resulting from the adoptive transfer of viable lymphocytes from donor during solid organ or hematopoietic stem cell transplant. Sometimes, it is very severe and may cause “unexplained” hemolysis during the postoperative period.
The authors reviewed literature about the PLS in liver transplantation.


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## Body

## 1. Introduction

The passenger
lymphocyte  syndrome is due to the production of antibodies by the donor B
lymphocytes “passenger lymphocytes” in a primary or secondary immune response against the recipient's red blood cell antigens [1].PLS is mostly often seen in solid
organ transplantation with a minor ABO mismatch [1]. The factors that affect
the severity of hemolysis including the quantity of transplanted lymphoid
tissue are: the level of red cells isoagglutinins in the donor before transplant and
the rapid rise in antibody titer in the recipient after transplant [2]. It
usually occurs in 1–3 weeks
posttransplant and resolves within 3 months posttransplant, and is a
self-limited process [3]. PLS usually results from antibodies active against
the ABO and Rh systems. Rarely, it may occur due to non-ABO/Rh antibodies,
particularly if the organ donor has been previously sensitized to other red
cell antigens by transfusion or pregnancy [4–7]. It has been reported that PLS
developed in two of four patients who got organs for a same donor [5].
Hemolysis due to PLS trends to be less common following solid organ transplant
[1, 3], and the relative frequency of PLS appears to be related to the volume of
transplanted lymphoid tissue. It is more frequent in heart and lung transplants
and less in liver and kidney transplants. Only few anecdotal cases are reported
in the literature after liver transplantation [1–5].


## 2. Definition of PLS

The appearance of unexpected antibodies of A and B specificity in
recipients of kidney allografts from ABO minor mismatched donors was first
reported in the early 1980s. Then, more than 100 cases involving liver, kidney,
pancreas, spleen, heart, lung, and heart-lung were published in 1991. The
source of the isohemagglutinins is viable donor B lymphocytes passively
transferred with the organ at the time of transplantation. The phenomenon has
been termed the “passenger lymphocyte syndrome.” The donor origin of the
antibody has been confirmed using immunoglobulin allotyping [1]. During PLS,
the donor memory B lymphocytes produce antibodies against recipient red blood
cells causing hemolysis [8]. A fascinating immunologic phenomenon can occur in
the setting of a minor ABO mismatch. Viable lymphocytes contaminating the donor
can temporarily reside in the recipient, and if they are stimulated shortly
after transplant by recipient or transfused red cell antigens, they can start
producing antibodies during their life. Leo et al. [9] reported that PLS with
severe hemolytic anemia was due to an anti-JKα on day 19 after allogeneic
peripheral blood progenitor cell transplantation.


## 3. Mechanism of PLS 3: Antibody (AB), Antigen (AG)

Three
different groups of ABO incompatibility can be distinguished in
transplantation: minor, major, and bidirectional ABO incompatibility. Major
ABO-incompatible (e.g., A into O) is characterized by the presence of preformed
antidonor A/B Ab directed  against donor ABO Ag expressed on transplanted cells.
Recipients of minor ABO-incompatible transplantation (e.g., O into A) express ABO Ag that are not expressed in the donor and are at risk for
graft-versus-host (GvH) reactions such as delayed hemolysis of recipient red blood cell (RBC) due to PLS.  Although major ABO-incompatible organs are not used routinely for
transplantation, minor ABO-incompatible organs are frequently used to meet the
demand for organs. Bidirectional ABO incompatibility (e.g., A into B) represents
a combination of major and minor ABO incompatibility and puts the recipient at
risk for both host-versus-graft and GvH [3].Therefore,
the PLS can be regarded as a type of graft-versus-host reaction. Most
commonly, passenger lymphocyte hemolysis is seen with a minor ABO mismatch,
although it can occur with other blood group system mismatches [3–7]. Immunocompetent donor memory B lymphocytes produce antibodies
in a secondary immune response against the recipient’s red cells. The massive
red cells destruction is thought to be complement-mediated [8]. Sokol et al.
[3] thought there were three different posttransplant immune-mediated hemolysis
which are
autoimmune hemolytic anemia, PLS, and major blood mismatch. PLS is most common
within the ABO system when there is a minor mismatch between the donor and the
recipient, although it can occur within other blood group system, such as Rh,
Kidd, and Lewis. Immunosuppression used posttransplantation has an important
etiologic role. Cyclosporine and tacrolimus can permit rapid proliferation of
spared lymphocyte B cells, which produce antibodies. The antibodies typically
become evident at 5 to 17 days after transplant, and are usually undetectable
by 3 months. It is rarely fatal. However during autoimmune hemolytic anemia, in
allogeneic bone marrow and/or peripheral blood progenitor cell transplants,
antibodies are produced by donor lymphocytes against donor-produced red cells.
While in solid organ transplants, antibodies are produced by recipient
lymphocytes against recipient red cells. Then, during major blood group
mismatch, recipient produces antibodies against donor red cells.


## 4. PLS in Solid Organ Transplantation

### 4.1. Liver Transplantation

The incidence of biochemical PLS in liver transplantation
is 30%–40%. In fact, in
almost all the cases (68–100%) the
antibodies are directed against Rh blood group antigens, and only 30–40% of these
antibodies led to immune hemolysis [1, 4, 10–13].Several reports have described the appearance of RBC
antibodies in patients receiving liver transplants from immunized donors. In
almost all of these cases, the antibodies were directed against Rh blood group
antigens, and only a few of these antibodies led to moderate-severe immune
hemolysis (anti-D, 13 cases, anti-c, 2 cases, and anti-e, 1 case)
[4, 11, 12, 14].PLS can develop abruptly and can vary from mild to severe. The
severity is mediated by the quantity of transplanted lymphoid tissue, donor
titers of isoagglutinins and a rapid rise in antibody titer in the recipient
after transplantation
[7]. Onset is usually 1–3 weeks
posttransplant and is a self-limited process, usually resolving by 3 months
posttransplant [13].In
particular, Triulzi et al. [14] reported that 56% (five out of nine) of liver
transplant recipients developed antibody, and five had biochemical (low
haptoglobin, high transaminases, and unconjugated bilirubin) evidence of
hemolysis. In Japan, it has been reported that two cases developed hemolytic
reaction due to graft-versus-host antibody in living donor liver
transplantation [11]. Shortt et al. [4] found that severe hemolysis due to PLS
in all three recipients of organs from a single donor with multiple red cell alloantibodies.
The liver transplant recipient required augmentation of immunosuppression to
treat immune hemolysis due to anti-B, -D, -C, and -Cellano (K). In
addition, Grosskreutz et al. [12] described HLA typing was critical diagnosis
of the recipient as Evans syndrome, and suggest that recipients of solid organs
from donors that are partially matched in the direction of rejection may need
to be closely monitored for graft-versus-host disease.


## 4.1. Liver Transplantation

The incidence of biochemical PLS in liver transplantation
is 30%–40%. In fact, in
almost all the cases (68–100%) the
antibodies are directed against Rh blood group antigens, and only 30–40% of these
antibodies led to immune hemolysis [1, 4, 10–13].Several reports have described the appearance of RBC
antibodies in patients receiving liver transplants from immunized donors. In
almost all of these cases, the antibodies were directed against Rh blood group
antigens, and only a few of these antibodies led to moderate-severe immune
hemolysis (anti-D, 13 cases, anti-c, 2 cases, and anti-e, 1 case)
[4, 11, 12, 14].PLS can develop abruptly and can vary from mild to severe. The
severity is mediated by the quantity of transplanted lymphoid tissue, donor
titers of isoagglutinins and a rapid rise in antibody titer in the recipient
after transplantation
[7]. Onset is usually 1–3 weeks
posttransplant and is a self-limited process, usually resolving by 3 months
posttransplant [13].In
particular, Triulzi et al. [14] reported that 56% (five out of nine) of liver
transplant recipients developed antibody, and five had biochemical (low
haptoglobin, high transaminases, and unconjugated bilirubin) evidence of
hemolysis. In Japan, it has been reported that two cases developed hemolytic
reaction due to graft-versus-host antibody in living donor liver
transplantation [11]. Shortt et al. [4] found that severe hemolysis due to PLS
in all three recipients of organs from a single donor with multiple red cell alloantibodies.
The liver transplant recipient required augmentation of immunosuppression to
treat immune hemolysis due to anti-B, -D, -C, and -Cellano (K). In
addition, Grosskreutz et al. [12] described HLA typing was critical diagnosis
of the recipient as Evans syndrome, and suggest that recipients of solid organs
from donors that are partially matched in the direction of rejection may need
to be closely monitored for graft-versus-host disease.


## 5. Other Solid Organ Transplantation

Ramsey [15] reported that the
frequency of PLS was highest, at 70% in heart-lung transplant recipients, and 17%
in kidney transplant recipients. Salerno et al. [6] reported a study of seven
minor ABO-incompatible lung transplant recipients identified antibody and
hemolysis in 57% (four out of seven) and 29% (two out of seven), respectively. It
has been suggested that the amount of lymphoid tissue transplanted with the
organ accounts for these differences. In addition, antibodies to red cell
antigens outside the ABO system have been reported in association with transplanted
kidney, pancreas-kidney, pancreas, liver, and heart-lung [1]. Seltsam et al.
[5] found development of donor alloantibodies in two recipients of separate
organs (liver and pancreas-kidney) from the same donor. Panaro et al. [7]
reported a severe hemolysis due to PLS in a living-related bowel transplant
recipient in an ABO-compatible donor-recipient pair (O into A).


## 6. Serological Features in PLS

Donor-derived ABO antibody typically develops 7–14 days after
liver transplantation. At the same time, direct antiglobulin test is always
positive. The serum antibody is predominantly IgG, but it may also be IgM.
Passenger lymphocyte derived antibodies are short-lived, persisting for about 2–3 weeks in liver transplant
recipients and 5 weeks in kidney transplant recipients [1]. Using flow
cytometry and nested polymerase chain reaction can diagnose the donor
lymphocyte microchimerism [5].


## 7. Clinical Features in PLS

PLS appears mostly in a variable
proportion of ABO minor mismatched organ transplant recipients. In liver transplant
recipients, from 68% [15] to 100% [14] with donor-derived antibody develop
hemolysis. Although the hemolysis is usually mild and self-limited, substantial
morbidity such as acute renal failure, disseminated intravascular coagulation,
hypotension, and multiorgan failure, has been reported [1, 14–18].


## 8. Treatment for PLS

Today, there are no reliable factors can
predict which recipients of ABO minor mismatched organs will develop passenger
lymphocyte derived antibodies or PLS. Management strategies for PLS
are anecdotal, as described in case reports and small series. Therapeutic
interventions include escalation of immunosuppression, immune modulation (e.g.,
by IVIG) and specifically targeting B-lymphocytes using monoclonal antibodies
such as rituximab [7].In
most cases PLS can be treated only with transfusions. Transfused red cells
should be of organ donor ABO group to replace susceptible red cells with cells
that would not be hemolyzed. Plasmapheresis or red cell exchange with
donor-type red cells may need to treat those who develop severe hemolysis.
Sometimes steroids is effective to treat PLS. Anti-CD20 monoclonal antibody
(rituximab) is also effective for the severe patients.There has been considerable interest in the past
several yearsin the use of the monoclonal antibodies widely used in
the treatmentof B-cell lymphoid neoplasms, namely rituximab
(Rituxan), and to a lesser extent alemtuzumab (Campath-1H).
Furthermore, the role of monoclonal antibodies specifically rituximab, in
the therapy of autoimmunecytopenias has been validated recently.
However, the experience with the monoclonal antibodies for the PLS in solid
organ transplantation is very limited. In fact up-to-date no experience was
reported in case of PLS after LT. It is likely thatas our
experience with the drug evolves, it will be used atan earlier
point in therapy, before more toxic immunosuppressives, rather than
only in refractory cases [19, 20].Panaro et al. [7] reported a case of severe
hemolysis due to PLS occurred in a 4-year-old blood group A recipient of living
donor (blood group O) small-bowel transplantation. The patient was treated successfully
with plasmapheresis, blood O transfusion, and rituximab. Sokol et al. [3]
reviewed the treatment of hemolysis due to PLS posttransplant
including transfusion of compatible red cells and/or plasma components with or
without steroids, and maintenance of adequate renal perfusion, plasma exchange
and/or exchange transfusion. Sometimes splenectomy should be considered.


## 9. Conclusion

Minor ABO mismatched organ
transplants are often used clinically. PLS is a common complication of this
practice. PLS can occur in 30%–40% of liver
transplant recipients including cadaveric and living donors. Today, no specific
treatment is available for the PLS. Therefore, PLS can be treated with
transfusion, plasmapheresis, red cell exchange, and anti-CD20 monoclonal
antibody.



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