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Part II
Pre-Heart Transplant Considerations
Listing Criteria and Optimization of the Pre-transplant Patient
Michelle M. Kittleson
5
Abstract
Once evaluation as a potential transplant
candidate is complete, there are still many
processes that a patient must undergo before
receiving a donor heart. All transplant candidates spend time on the waitlist after listing;
the current donor heart shortage means that,
unfortunately, waitlist mortality remains a
significant problem. This chapter aims to provide an overview of the listing process, the
current US system of heart allocation, medical surveillance, immunological optimization,
and other considerations of patients on the
waiting list.
Keywords
Heart failure · Heart
transplantation · Allocation · Policy · Donor
heart
M. M. Kittleson (*)
Cedars-Sinai Smidt Heart Institute, Los Angeles,
CA, USA
e-mail: michelle.kittleson@cshs.org
Clinical Pearls
• Heart Transplant Candidates undergo rigorous
evaluation, culminating in multi-disciplinary
selection meetings that include transplant and
heart failure (HF) cardiologists, transplant
surgeons, a psychiatrist, social workers, transplant coordinators, apharmacist, and a dietician, to determine suitability for transplant.
If approved, the patient is then listed for
transplant.
• Advantages of the new 2018 six-tiered heart
allocation system include prioritization of
more unstable inpatient candidates,such as
those with ECMO support (Status 1), over
those receiving inotropic support with hemodynamic monitoring (Status 3).
• Once listed, patients should be fre-
quently clinically reevaluated and managed accordingly, taking into account HF
symptoms,hemodynamic stability, and exercise capacity as priority status may change.
•
Factors associated with increased HTx wait-
list mortality include older age, lower BMI,
male sex, diabetes, dialysis, poorfunctional
status at listing, and higher urgency status.
• Patients on the heart transplant waitlist
should be monitored at least annually for the
detection of circulating anti-HLA antibodies,
as these may decrease the donor pool while
awaiting an immunologically compatible
donor.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2025
J. Kobashigawa (ed.), Clinical Guide to Heart Transplantation, https://doi.org/10.1007/978-3-031-88290-6_5
53
54 M. M. Kittleson
• Special considerations for patients on the
waitlist include a switch from DOAC to
Coumadin, discontinuation of antiplateletdrugs to minimize perioperative bleeding.
• Monitoring of waitlist patients with pulmonary hypertension with regularly scheduled
echocardiograms (at least q 6 months)and/or
intra-pulmonary artery device may be helpful
to avoid right ventricular failure of the donor
heart at the time of implantation.
Listing Process
Once evaluation as a potential transplant candidate is complete, there are still many processes
that a patient must undergo before receiving
a donor heart. All transplant candidates spend
time on the waitlist after listing; the current
donor heart shortage means that, unfortunately,
waitlist mortality remains a significant problem
[1]. As described in Chaps. 3 and 4, heart transplant (HTx) candidates undergo rigorous medical and psychosocial evaluation for transplant
suitability. In most institutions, the culmination
of this process is a final review of relevant information at regularly scheduled multi-disciplinary
meetings, including the transplant and heart
failure (HF) cardiologists, transplant surgeons,
other physicians involved with the patient’s care,
psychiatrist, social workers, transplant coordinators, pharmacist, and dietician. At these
meetings, a final decision regarding suitability
for transplant is made, and the patient, if suitable, is listed for transplant. The HTx waiting
list is a national, computerized list that is managed and maintained by the Organ Procurement
and Transplantation Network (OPTN). Listing
includes relevant recipient patient variables,
including patient name, weight, weight range
of acceptable donors, blood group, unacceptable antigens, immunological virtual crossmatch
data, and whether a prospective crossmatch will
be required (for highly sensitized patients) at
the time of donor selection. Each patient is also
assigned an urgency status code according to
the priority level on the list (see below for more
details). Within a status code level, candidates
are ordered by time spent on the waiting list. As
a donor becomes available, the donor's heart is
offered to the highest recipient on the list that
matches in terms of sizing, weight, blood group,
and immunological criteria; if declined, the
heart is offered to the next candidate on the list.
Allocation Criteria
A Brief History
The National Organ Transplant Act, which was
enacted by Congress in 1984, was responsible
for the formation of the OPTN, a unified transplant network that governs organ transplantation
in the United States. Since the inception of the
OPTN, allocation policy has undergone several iterations. A formal urgency-based system
was first adopted in 1988 by the Department of
Health and Human Services (DHHS). Initially,
there were only two status levels: Status 1 and
Status 2, with the sickest patients in Status 1,
and others in Status 2 [2, 3]. Further major
revisions occurred in 1999, with the introduction of a higher priority level for sicker Status
1 patients, dividing the Status 1 classification
into Status 1A and 1B. The Final Rule, issued
by the DHHS in 2000, dictated that policy
must attempt to balance the difficult combination of equitable organ allocation (including
across regions) while prioritizing according to
severity of illness. Unfortunately, unlike kidneys, explanted hearts are currently only viable
for a maximum of 4–6 h, so allocation needs to
be delineated within geographic regions, further affecting distribution equity. In an update
in 2005, patients listed for cardiac transplantation were stratified into a three-tiered system of
escalating urgency for HTx to enhance broader
access to donors. By 2015, the sickest patients
in the Status 1A tier increased 5-fold and
accounted for two-thirds of HTx recipients [4].
5 Listing Criteria and Optimization of the Pre-transplant Patient
55
The 2018 Allocation Revision
with poorer prognosis, those with infiltrative or
hypertrophic cardiomyopathy (Status 4), over
Despite good intentions to optimize organ
allocation, there were critiques of the 2005
system [4] namely that the former Status 1A
provided inadequate resolution among the
sickest patients: a heterogenous group of
unstable HTx candidates received the same
prioritization despite different waitlist mortality [2]. The Thoracic Organ Transplantation
Committee redesigned a six-tiered heart allocation system with a broader geographic sharing policy, implemented on October 18, 2018
(Table 5.1).
Advantages of the new system include prior-
itization of more unstable inpatient candidates,
such as those with ECMO support (Status 1),
over those receiving inotropic support with
hemodynamic monitoring (Status 3), as well
as prioritization of ambulatory HTx candidates
Table 5.1 Heart transplant allocation system as of October 2018
Status Status description
1 VA-ECMO
Non-dischargeable surgically implanted Bi-VAD
LVAD with life-threatening VT or VF
2 Non-dischargeable surgically implanted LVAD
IABP
Life-threatening VT or VF
LVAD with mechanical failure, admitted to the hospital
Percutaneous endovascular pump (e.g. Impella
TAH, Bi-VAD, RVAD, or VAD for single ventricle patient
3
4
5 Listed for heart transplant and at least one other organ
6 All other adult heart candidates not meeting higher Status
7 Inactive
LVAD discharged with discretionary 30 days
LVAD with device infection, hemolysis, pump thrombosis, right heart failure, mucosal
bleeding or aortic regurgitation
Multiple inotropes or single high dose inotrope with PA catheter
VA-ECMO, IABP, or percutaneous endovascular pump that downgrades
Dischargeable LVAD without discretionary 30 days
Multiple inotropes or single high dose inotrope without PA catheter
Congenital heart disease, refractory angina, re-transplantation
Amyloidosis, Hypertrophic or Restrictive cardiomyopathy
those with nonischemic dilated cardiomyopathy
(Status 6). There have been significant shifts in
HTx practices and patient outcomes following
the implementation of the new policy, including changes in listing practices, waitlist time and
mortality, transplant donor characteristics, posttransplantation outcomes, and mechanical circulatory support use (Fig. 5.1) [5].
In a comparative analysis of the 2 eras, a
larger proportion of transplantation procedures
(78 vs. 68%) were performed in the highest-priority patients following the policy change [6].
Interestingly, an analysis that applied the new
risk stratification rules to candidates from the
pre-policy era demonstrated 17% more status
2 listings than anticipated, corresponding to the
observed increase in the use of IABP, and the
odds of high-priority listing were 5 times greater
®
)
Source Publicly available at: https://optn.transplant.hrsa.gov/media/km0bko0h/adult_heart_criteria.pdf
VA-ECMO, Veno-arterial extracorporeal membranous oxygenation; Bi-VAD, Biventricular assist device; LVAD, Left
ventricular assist device; VT, Ventricular tachycardia; VF, Ventricular fibrillation; IABP, Intra-aortic balloon pump;
®
Impella
(ABIOMED Inc., Danvers MA, USA); TAH, Total artificial heart; RVAD, Right ventricular assist device
56 M. M. Kittleson
Status 1-3
Similar post-
transplant
Increased
travel and
survival
2018
Change
Less durable
LVAD with
lower
transplant
rate
More ECMO,
IABP with
significant
center
Fig. 5.1 Summary of the impact of 2018 Allocation Change. ECMO = extracorporeal membrane oxygenation;
IABP = intra-aortic balloon pump; ICU = intensive care unit; LVAD = left ventricular assist device
Shorter
and lower
waitlist
mortality
than expected following the policy change
despite similar candidate characteristics [7]. On
the other hand, the placement of durable mechanical circulatory support devices has decreased
[8, 9]. Without a clear change in candidate characteristics nor overall number of listings, these
phenomena may reflect a concerted change in
clinical practice by transplant providers to meet
the new high-priority criteria for patients that had
lower urgency by previous era criteria. Despite
a greater proportion of highest priority additions
(statuses 1–3) to the waitlist in the new era, waitlist mortality is similar in some studies and even
reduced in others, both at 90 days and 1 year
[10, 11]. Despite the highest priority listings in
the new era, the similar, if not improved, waitlist mortality is suggestive of the policy change
functioning as intended, although further data
will continue to assess waitlist outcomes.
Optimization of the Pre-transplant Patient
Medical Surveillance on the Waitlist
Medical treatment of HF and the evaluation
criteria for HTx candidacy have already been
covered in Chaps. 1–4. However, even once
listed, patients should be frequently clinically
reevaluated and managed accordingly, taking into account HF symptoms, hemodynamic
stability (including blood pressure and EF
5 Listing Criteria and Optimization of the Pre-transplant Patient
Table 5.2 Guidelines for consideration of inactivation of heart transplant waitlist candidates due to clinical
improvement
Clinical criteria Exercise criteria (assuming initial
peak oxygen consumption of <14 ml/
kg/min)
• Stable fluid balance without orthopnea, elevated jugular venous pressures
or other evidence of congestion
• Stable blood pressure with systolic ≥ 80 mmHg
• Stable serum sodium (≥133 mEq/L)
• Stable renal function (BUN < 50 mg/dl, creatinine < 2 mg/dl)
• Absence of symptomatic ventricular arrhythmia
• Absence of frequent angina
• Absence of severe drug side effects
• Stable or improving activity level without dyspnea during self-care or
1-block exertion
• Increasing ejection fraction by echocardiogram
Reused with permission: Michelle Kittleson, Jon Kobashigawa, Minh Luu, Listing, Donor Allocation and and Optimization of the Pre-transplant Patient, Clinical Guide to Heart Transplantation, 37–45, 2017, Springer Nature; https://
doi.org/10.1007/978-3-319-43773-6_4
• Improvement in peak oxygen
consumption of ≥2 mg/kg/min
• Peak oxygen consumption of
≥14 ml/kg/min
57
by echocardiography), and exercise capacity.
Serum electrolytes and renal function should
also be reviewed. The general aim is to maintain
or even improve the level of function at listing
until transplantation, essentially to make sure
each patient remains an optimal candidate and is
appropriately risk-stratified. A formal reevaluation on a yearly basis is required to reassess each
patient’s ongoing candidacy for transplant. A
significant number of patients initially listed for
transplantation may have clinical improvement,
no longer requiring active transplant listing. In
these cases, the patient should still undergo exercise testing, clinical evaluation, and hemodynamic assessment every few months. A detailed
list of criteria for inactivation of HTx candidates
due to clinical improvement is given in Table 5.2
Alternatively, some patients may have further
clinical deterioration, requiring the difficult task
of delisting them. Ideally, palliative care teams
should be involved with all patients evaluated
and undergoing HTx to assist with the complex
issues involved. Pre-transplant outcomes indicate that 1-year survival on the HTx waiting list
was 63.9% between 2007 and 2017 [12]. Thus,
vigilance for indications of worsening HF or
complications related to HF is crucial in both the
inpatient and outpatient waitlist candidates.
In the outpatient waitlist candidate, such a
scenario should necessitate immediate admission
for evaluation and appropriate treatment.
Likewise, inpatients should be monitored daily
for the above. Ultimately, the goal is to prevent
conditions that may subsequently negatively
affect the perioperative outcomes, as well as
death on the waitlist. A full list of indications for
readmission is summarized in Table 5.3. Factors
associated with increased HTx waitlist mortality include older age, lower BMI, male sex, diabetes, dialysis, poor functional status at listing,
and higher urgency status [12]. These patients
should, therefore, be monitored especially
closely. Should a patient deteriorate and consequently display a relative contraindication to
transplantation, the patient is placed on the inactive list (Status 7), and medical or device therapy
is administered as appropriate. Once the patient
has improved, the patient is reevaluated for transplanted suitability and is able to return to the
transplant list without penalty (i.e., the time previously spent on the waitlist is counted).
Immunological Optimization
While this topic will only be touched upon
briefly here (it is covered in greater detail in
Chap. 12), a notable proportion of waitlist
patients display elevated levels of circulating
anti-HLA antibodies as well as donor-specific
58 M. M. Kittleson
Table 5.3 General indications for admission of waitlist candidates
• Unstable angina
• Syncope
• Frequent implantable cardioverter-defibrillator discharges
• Suspected embolic event
• Refractory congestive symptoms despite compliance with increased diuretics, which may:
– Render patients bedridden
– Cause increased hepatic congestion
– Worsen pre-existing pulmonary hypertension
• Persistently low blood pressure < 80 mmHg
• Pulse pressure < 12 mm Hg with cool extremities
• Chronic renal failure, creatinine > 2 mg/dl
• Clinical evidence of severe or progressive low cardiac output
• Clinical or catheterization evidence of severe pulmonary hypertension (systolic PA pressure > 60 mmHg)
Reused with permission: Michelle Kittleson, Jon Kobashigawa, Minh Luu, Listing, Donor Allocation and and Optimization of the Pre-transplant Patient, Clinical Guide to Heart Transplantation, 37–45, 2017, Springer Nature; https://
doi.org/10.1007/978-3-319-43773-6_4
anti-HLA antibodies. These anti-HLA antibodies may develop from events such as previous
pregnancy, prior blood transfusions, or implantation of a mechanical circulatory support device.
Patients with high levels of circulating antiHLA antibodies are considered “sensitized”
and, as a cohort, demonstrate poorer outcomes
post-transplant [13], including increased rejection (acute and chronic) and increased mortality.
Furthermore, the chances of an immunologically
compatible donor are much lower. Therefore,
any events such as blood transfusions need to
be documented and preformed antibody levels
rechecked, with leukocyte filtered blood administered whenever possible to reduce the risk of
further sensitization. Desensitization therapy is
an option for end-stage HF waitlist patients who
are highly sensitized and would otherwise have
a low chance of finding an acceptable donor
organ [14, 15]. Desensitization may include
intravenous immune globulin, rituximab, bortezomib, or tocilizumab [16]. In highly sensitized
patients for whom a donor becomes available, a
prospective crossmatch will also be performed
shortly before transplant. The purpose is to
definitively identify donor hearts that would be
at risk of exposure to the specific circulating
cytotoxic antibodies of the potential recipient.
The need to physically transport the recipient’s
blood to the donor location reflects a geographical limitation of transplant in these highly sensitized patients.
Other Considerations for Patients on the Waitlist
Patients on anticoagulation with one of the novel
oral anticoagulants or on antiplatelet agents such
as clopidogrel or prasugrel may be changed to
more easily reversible options, since there may
be little time from notification to the surgical procedure. Patients with histories of recent
cigarette or other drug use should have periodic
toxicology screening while waiting. All patients
should be monitored for adherence to visits and
the medical regimen and instructed to notify the
team of any change in their medical condition
or residence to reinforce the importance of these
factors post-transplant. Once a donor heart is
made available, the patient is typically contacted
by the on-call transplant coordinator and if an
outpatient, promptly admitted. The patient is told
to refrain from eating or drinking. A brief reevaluation of the potential recipient is performed
to ensure that they have not developed any contraindications that may compromise the goals of
early management post-transplant. The pre-transplant evaluation summaries should be reviewed
for any additional comorbidities or conditions
which may require specialized care during and
after the transplant operation. For example,
patients with pre-existing arrhythmias who are
on amiodarone must be carefully watched, as
this medication can slow the donor heart rate
post-transplantation. A final compatibility check
595 Listing Criteria and Optimization of the Pre-transplant Patient
is run, including checking whether the blood
type matches appropriately and whether the
donor is of an appropriate size for the patient’s
height and weight. Pre-operative management
includes special considerations for those with a
history of pulmonary hypertension, as well as
those with a predilection for increased bleeding.
In those with pre-existing pulmonary hypertension, placement of a pulmonary artery catheter
and measurement of pulmonary artery pressure is recommended prior to transplantation. If
necessary, pharmacological adjustment through
selective vasodilation to reduce pulmonary artery
pressure should be performed, in order to prevent
acute right HF of the donor heart. Information
based on this may also be used to make a final
decision regarding whether to accept the donor
heart, especially where the donor heart is undersized. For those recipients at risk of increased
intra-operative bleeding (usually due to previous sternotomy, mechanical circularity support
device, long-term right HF, or chronic warfarin therapy), vitamin K (10 mg subcutaneously)
and fresh frozen plasma may be administered
prophylactically prior to the operation. Standard
pre-operative measures also include immunosuppression, such as administration of pre-operative
corticosteroids at some centers (500 mg IV 4 h
before transplantation; 250 mg IV 1 h before),
as they are thought to help reduce the damaging inflammatory processes that are the result
of cardiopulmonary bypass. At some centers,
pre-operative administration of anti-proliferative
and calcineurin inhibitors occurs, whereas other
centers prefer to initiate these agents’ peri-operatively or shortly after transplant. Pre-operative
broad-spectrum antibiotic prophylaxis is also
administered to protect against gram-positive
and gram-negative organisms.
References
1. Colvin M, Smith JM, Ahn Y, Skeans MA, Messick
E, Bradbrook K, et al. OPTN/SRTR 2020 annual
data report: heart. Am J Transplant. 2022;22(Suppl
2):350–437.
2. Meyer DM, Rogers JG, Edwards LB, Callahan ER,
Webber SA, Johnson MR, et al. The future direction
of the adult heart allocation system in the United
States. Am J Transplant. 2015;15(1):44–54.
3. Van Meter CH. The organ allocation controversy:
how did we arrive here? Ochsner J. 1999;1(1):6–11.
4. Committee OUTOT. Proposal to modify the adult
heart allocation system. 2016.
5. Maitra NS, Dugger SJ, Balachandran IC, Civitello
AB, Khazanie P, Rogers JG. Impact of the 2018
UNOS heart transplant policy changes on patient
outcomes. Heart Fail. 2023;11(5):491–503.
6. Goff RR, Uccellini K, Lindblad K, Hall S, Davies R,
Farr M, et al. A change of heart: preliminary results
of the US 2018 adult heart allocation revision. Am J
Transplant. 2020;20(10):2781–90.
7. Ran G, Chung K, Anderson AS, Gibbons RD,
Narang N, Churpek MM, et al. Between-center variation in high-priority listing status under the new
heart allocation policy. Am J Transplant. 2021.
8. Jawitz OK, Fudim M, Raman V, Bryner BS, DeVore
AD, Mentz RJ, et al. Reassessing recipient mortality under the new heart allocation system: an
updated UNOS registry analysis. JACC Heart Fail.
2020;8(7):548–56.
9. Clerkin KJ, Salako O, Fried JA, Griffin JM,
Raikhelkar J, Jain R, et al. Impact of temporary
percutaneous mechanical circulatory support before
transplantation in the 2018 heart allocation system.
Heart Fail. 2022;10(1):12–23.
10. Stern LK, Velleca A, Nishihara K, Shen A,
Zaliznyak M, Patel J, et al. Impact of the United
Network for organ sharing 2018 donor heart allocation system on transplant morbidity and mortality.
Clin Transplant. 2021;35(2):e14181.
11. Kilic A, Mathier MA, Hickey GW, Sultan I, Morell
VO, Mulukutla SR, et al. Evolving trends in adult
heart transplant with the 2018 heart allocation policy
change. JAMA Cardiol. 2021;6(2):159–67.
12. Bakhtiyar SS, Godfrey EL, Ahmed S, Lamba
H, Morgan J, Loor G, et al. Survival on the
heart transplant waiting list. JAMA Cardiol.
2020;5(11):1227–35.
13. Kransdorf EP, Pando MJ, Gragert L, Kaplan B.
HLA population genetics in solid organ transplantation. Transplantation. 2017;101(9):1971–6.
14. Kobashigawa J, Colvin M, Potena L, Dragun D,
Crespo-Leiro MG, Delgado JF, et al. The management of antibodies in heart transplantation:
an ISHLT consensus document. J Heart Lung
Transplant. 2018;37(5):537–47.
15. Kobashigawa J, Mehra M, West L, Kerman R,
George J, Rose M, et al. Report from a consensus conference on the sensitized patient awaiting
heart transplantation. J Heart Lung Transplant.
2009;28(3):213–25.
16. DeFilippis EM, Kransdorf EP, Jaiswal A, Zhang X,
Patel J, Kobashigawa JA, et al. Detection and management of HLA sensitization in candidates for
adult heart transplantation. J Heart Lung Transplant.
2023;42(4):409–22.
Overview of Transplantation Immunobiology
Xiaohai Zhang
6
Abstract
Immunosuppression after heart transplantation has significantly reduced the incidence
of rejection and improved patient outcomes.
However, long-term graft outcome is challenged by multiple factors, including the
effects of the immunosuppressive drugs used
and the chronic rejection process. A better
understanding of the multiple mechanistic
processes involved may provide evidence of
the feasibility of the best approach to achieve
the ultimate goal of donor-specific tolerance.
This chapter will summarize the role of the
immune systems in transplantation, focusing
on the interaction between innate and adaptive immunity, Human Leukocyte Antigens
(HLA) polymorphism and nomenclature, and
outlines the pathways of alloantigen presentation. The chapter also covers T cell-mediated
rejection, antibody responses, and immunosuppressive strategies and explores the concept of tolerance.
X. Zhang (*)
HLA and Immunogenetics Laboratory, Comprehensive
Transplant Center, Cedars-Sinai Medical Center, Los
Angeles, CA, USA
e-mail: xiaohai.zhang@cshs.org
Keywords
Heart failure · Heart transplantation · Human
leukocyte antigen · Major histocompatibility
complex · Rejection · Antibodies · Donorspecific antibodies · T-cells · B-cells ·
Tolerance
Clinical Pearls
• Both the innate and adaptive immune systems
normally collaborate to mount a response to
external pathogens, but the same mechanisms
also play a role in allograft rejection and
injury.
• Mismatched HLA alloantigens on the donor
graft are targeted by the recipient’s immune
system.
• Donor graft alloantigens are presented to the
recipient’s T-cells through the indirect, direct,
or semi-direct pathway, ultimately leading to
CD8+ T-cell-mediated cytotoxic response;
various effector T-cell subsets are implicated
in the cellular rejection process.
• Alloantibodies to the donor graft, originating
from plasma cells, damage the graft through
complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity through
natural killer cell recruitment, and endothelial
activation.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2025
J. Kobashigawa (ed.), Clinical Guide to Heart Transplantation, https://doi.org/10.1007/978-3-031-88290-6_6
61
62 X. Zhang
• CD-20 is expressed on surfaces of B-cells
and can be targeted by anti-CD20 monoclonal antibodies such as rituximab to reduce
alloantibody production and thus subsequent
antibody-mediated rejection.
• Bortezomib is a proteasome inhibitor used to
inhibit antibody production by plasma cells.
• Tolerance may theoretically be induced by
induction of chimerism, depletion of specific
lymphoid tissues, costimulatory blockade and
regulation through B-cell mechanism.
Innate Versus Adaptive Immunity
The immune system protects us from infection
by recognizing and destroying or containing
pathogens. The immune system can be categorized into two branches: the innate immune
system and the adaptive immune system. The
innate immune system and adaptive immune
system are not completely independent systems.
Instead, there is crosstalk at multiple levels and
collaboration with each other to mount immune
responses to pathogens. The processes that initiate transplant-directed alloimmune responses
are not mediated by components related to organ
transplantation, but rather are developed from a
system that maintains the integrity against various pathogens. Exposure to pathogens such as
viruses, bacteria, fungi, and protozoa is first
countered by the innate immune system composed of inflammatory cells, usually granulocytes, which include neutrophils, eosinophils,
basophils, and mast cells. A second important cellular component of the innate immune
response includes monocytes, macrophages,
and dendritic cells, which can take up and process exogenous materials. Also included in the
cellular innate immune response are the γδ and
natural killer (NK) cells, which can kill virally
infected cells without prior sensitization [1].
These same cells survey the periphery, including transplanted organs, with usually a slower
response than that observed in innate immune
responses against pathogens. The cellular components of the adaptive immune response
include T and B cells, which express unique and
polymorphic antigen receptors, T cell receptor
(TCR), and B cell receptor (BCR). The process
that generates the antigen-detecting region of
these receptors provides the ability to recognize
and potentiate the response to specific antigens,
which may include pathogens but also self-antigens. During this process, T and B cells undergo
a selective maturation process, which removes
strongly binding, autoreactive cells. When an
organ transplant occurs between genetically
disparate individuals, T cell-mediated adaptive immune response must be addressed with
immune modulation. The cells of the innate
immune component also play a role in presenting the alloantigen to these T cells. The activated
T cells can also help B cells produce alloantibodies as part of the humoral response, thereby
damaging the graft. Further details of these
cells that participate in the transplant immune
response are included later in this chapter.
Human Leukocyte Antigens Polymorphism and Nomenclature
Overview and Polymorphism of HLA
The difference between proteins expressed by
the recipient and donor is actively surveyed by
the recipient’s immune system. The most polymorphic proteins in humans are the human leukocyte antigens (HLA). More than 30,000 HLA
alleles have been identified by the year 2023.
The high degree of polymorphism is necessary
for HLA molecules to present various peptides
during the adaptive immune response to pathogens; however, this degree of polymorphism
creates a substantial barrier to allo-transplant
between individuals. It is very common for the
donor and recipient to not share exactly the
same HLA molecules. The mismatched HLA
molecules are recognized as foreign and often
targeted by the recipient’s immune system. In
humans, HLA molecules are encoded by a cluster of genes localized on chromosome 6. The
HLA genes are grouped into two categories