Transplantation

Transplantation
Reviewed by Sirapassorn
Sornphiphatphong, M.D.

Overview
• Definition in transplantation
• Adaptive immune responses to allografts
• Graft rejection
• Hematopoietic Stem Cell Transplantation

Overview of Hematopoietic Stem
Cell Transplantation
• Sources of HSCT
• Donor selection and manipulation
of the graft
• Complications of HSCT
– Graft rejection
– Graft-versus-host disease
• HSCT for The Treatment of Primary
Immunodeficiency Disorders

Transplantation
• Treatment for replacement of non-functioning
organs and tissues with healthy organs or
tissues
• Increasing during the past 45 years
• Hematopoietic stem cells, kidneys, livers, and
hearts
Abbas AK, et al. Cellular and molecular immunology Ed 8th

Transplantation
• Graft: cells, tissues, or organs
• Donor: provides the graft
• Recipient, host: who receives the graft
• Orthotopic transplantation; normal anatomic
location
• Heterotopic transplantation: different site

Transplantation
• Autologous graft: to the same individual
• Syngeneic graft: two genetically identical
individuals
• Allogeneic graft, allograft: between two
genetically different individuals of the same
species
• Xenogeneic graft , xenograft: different species

Adaptive immune responses
to Allografts
• Ag that stimulate adaptive immune responses
against allografts are histocompatibility
proteins
• Strong rejection reactions; major
histocompatibility complex (MHC) molecules
• Weak or slower rejection reactions; minor
histocompatibility antigens

Adaptive immune responses
to Allografts
• Allogeneic MHC molecules of a graft can be
presented for recognition by the recipient’s T
cells in 2 different ways; the direct and indirect
pathways
• Direct allorecognition can generate both
CD4+ and CD8+ T cells that recognize graft
antigens and contribute to rejection

Graft rejection
• Classified on the basis of histopathologic
features and the time course of rejection
after transplantation
Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd

Hyperacute Rejection
• Thrombotic occlusion of the graft vasculature
• Within minutes to hours after host blood vessels
are anastomosed to graft vessels
• Mediated by preexisting antibodies in the host
circulation that bind to donor endothelial antigens

Acute Rejection
• Injury to the graft parenchyma and blood vessels
mediated by alloreactive T cells and antibodies
• Several days to a few weeks
• Immunosuppression

Chronic Rejection and Graft
Vasculopathy
• In the kidney and heart: vascular occlusion and
interstitial fibrosis
• Lung transplants: thickened small airways (called
bronchiolitis obliterans)
• Liver transplants: fibrotic and non-functional bile ducts

Prevention and Treatment of
Allograft Rejection
• Minimize alloantigenic differences between
the donor and recipient
• ABO blood typing: avoid hyperacute rejection
• HLA alleles
– HLA-A, HLA-B, and HLA-DR
– Zero-antigen mismatches predict the best
survival

Hematopoietic Stem Cell
Transplantation

Hematopoietic Stem Cell
Transplantation
• HLA discovery in 1968
• Human stem cell transplantation (HSCT)
provide treatment for a variety of
congenital and acquired disorders; SCID
in 1968

Sources of hematopoietic stem
cells for transplantation

Bone marrow stem cells
• Multiple aspirations along the iliac crests under
general anesthesia
• 500 mL- 1 L depended on the type of transplant and
on the weight of the recipient
• HLA-identical transplantation
– injected intravenously without further manipulation
into a central line in the recipient
• Mismatched transplantation
– T-cell depleted and injected intravenously

Peripheral blood stem cells
• G-CSF to the donor, 10 μg/kg/day x 5 days
• Purified by positive selection, enumerated and
injected
Cord blood
• Collected in heparinized medium and stored in
liquid nitrogen, and small aliquots are preserved
for HLA typing
• Thawed and injected into the recipient without
further manipulation

Donor selection and manipulation
of the graft

HSCT from a related HLA-identical donor
• Best for rapid engraftment and immune
reconstitution
• The mature T cells contained in the graft provide
a first line of immune reconstitution after
transplant
• Rapid increase circulating T lymphocytes 2
weeks after HSCT

HSCT from a haploidentical donor
• No such donor is available
• based on the ability of donor-derived stem cells
to repopulate the recipient’s vestigial thymus
and give rise to fully mature T lymphocytes
• life-saving procedure of SCID infants

T-cell depletion
• Soybean lectin: agglutination of mature marrow cells and
removed by sedimentation
• E-rosetting (with sheep erythrocytes) and density
gradient centrifugation
• Incubation of the marrow with monoclonal
antibodies to T lymphocytes plus complement;
Campath-1G, Leu 1
• Positive selection of CD34+ cells using monoclonal
antibody affinity

HSCT from matched unrelated donors
• Increasingly used to treat severe primary
immunodeficiencies
• Bone Marrow Donors Worldwide (BMDW)
registry
• 3–4 months to identify a MUD
• Preparative chemotherapy regimen in the
recipient (even in the case of SCID) and graft
versus-host prophylaxis

HSCT using unmanipulated cord blood
• Lower risk of GvHD than with MUD
• Based on the urgency of the transplant, the cell
dose required, and the number of HLA
disparities
• Requires pre-transplant conditioning and GvHD
prophylaxis, irrespective of the underlying
disease

Complications of hematopoietic
stem cell transplantation
• Conditioning regimen toxicity
– affect several organs e.g. busulfan-lung
damage, veno-occlusive disease
– anemia, thrombocytopenia, and leukopenia
• Graft rejection
• Graft-versus-host disease
• Infections

Graft rejection
• Immunocompetent cells in the host
specifically recognize and react to donor-
derived stem cells
– the degree of immunocompetence of the host
– the degree of HLA disparity
– the number of stem cells infused
– the type of conditioning regimen used
– the possible pre-sensitization of the host to
donor histocompatibility antigens

Graft rejection
• SCID, graft rejection unlikely because of
the profound immunodeficiency
• Regimen: busulfan + cyclophosphamide,
± antithymocyte globulin (ATG)
• Phagocytic or hemophagocytic cell
disorders, a more aggressive conditioning
regimen

Acute graft-versus-host disease
• Donor-derived T lymphocytes to the recipient’s
antigens
• Early as 1 week after HSCT
• Potentially fatal
• The major risk factors for aGvHD include
– HLA mismatch
– Older age of the recipient
– Gender mismatch
– Prior herpes virus infection

Acute GvHD
• Highgrade fever, MP rash (confluent),
exfoliative dermatitis, diarrhea, and liver
abnormalities (hepatomegaly, ↑elevated
liver enzymes, jaundice), protein-losing
enteropathy, abdominal pain
• Third space loss
• Bone marrow aplasia, high susceptibility to
infections

Chronic GvHD
• Symptoms persist or appear after 100 days
• Skin changes (scleroderma-like lesions,
hyperpigmentation, hyperkeratosis, skin atrophy,
ulcerations), tissue fibrosis, limitation of joint
motility
• Fibrosis of exocrine glands (sicca syndrome),
fibrosis of lungs and liver, immune dysregulation
and autoimmunity

Chronic GvHD
• Acute GvHD represents a major risk factor for
cGvHD
• Older age of the recipient
• Transplantation from a multiparous female donor
into a male recipient
• Minor histocompatibility incompatibility

Prevention of GvHD
• Fully matched donor
• T-cell depleted HLA-mismatched donor
• Pharmacological GvHD prophylaxis
– Cyclosporine A daily for 6 months,
or methotrexate (15 mg/m2 on the first day, and then
10 mg/m2 at day 3, 6
– or combination
– ATG

Treatment of GvHD
• Immunosuppressive drugs
• Steroids, ATG, mycophenolate mofetil,
cyclosporine A, monoclonal antibodies directed
to HLA (anti-CD3) or to Th1-type cytokines (anti-
TNF-α) and cytokine receptors (anti-CD25,
daclizumab)
• Topical steroids and calcineurin inhibitors may
alleviate mucosal and skin symptoms
• Ursodeoxycholic acid may be useful in cGvHD
with significant liver involvement

Infections
• Adenovirus, CMV, EBV, parainfluenzae III
virus. PCP, aspergillus, bacterial infection
• Viral infection after HSCT may cause
interstitial pneumonia, enteritis, and
encephalitis
• EBV cause B-cell lymphoproliferative
disease (BLPD)

HSCT for The Treatment of
Primary Immunodeficiency
Disorders

HSCT for SCID
• Immune suppression is not required
• No conditioning regimen is necessary in related
HLA-identical donor
• US centers adopt same policy for T cell-depleted
mismatched HSCT
• European centers tend to use conditioning
regimens prior to mismatched or MUD HSCT,
particularly in SCID with residual autologous NK

Survival following HSCT for SCID
• Related HLA-identical, MUD, and T cell-depleted
haploidentical HSCT were 100%, 94%, and 52%,
respectively
• Has improved over the years

Factors influence survival
• Younger age at transplantation leads to superior
survival
– Among 38 infants who were treated by Buckley and
collaborators before 3.5 months of age, 37 (97%)
have survived
• Co-trimoxazole prophylaxis for recipients
• Absence of pre-transplant pulmonary infection
among recipients
• Type of SCID

Factors influence survival
• Survival following related HLA-mismatched
HSCT is better in infants with B+ SCID than with
B− SCID (64% vs 36%, respectively)
• The poorer outcome in infants with B− SCID
may reflect the presence of autologous NK cells
detectable in most of these infants

Complications following HSCT for SCID
• 56% of all deaths were due to infections,
25% to GvHD, and 5% to BLPD (B-cell
lymphoproliferative disease)
• Immune dysregulation and autoimmunity

Quality and kinetics of T-cell
immune reconstitution
• The effectiveness of HSCT in SCID: the
normalization of the number and function of T
lymphocytes
• Reconstitution differs substantially depending on the
type of transplantation
• The kinetics of T-cell reconstitution influenced by the
recipient’s age
• Early transplantation (<3.5 months of age) leads to
superior thymic output

Related HLA-identical donor
• The unmanipulated graft
contains mature T
lymphocytes
• expanded in 2 weeks
• Oligoclonal, have a
memory (CD45R0)
phenotype
• Fully competent, and
provide the recipient with
functional immunity
MUD
• Present mature T cells
• Conditioning regimen
partly impairs immune
development
• Naive (CD45RA+ CD31+)
T lymphocytes appear in
3–4 months
• Number tends to peak 1
year after HSCT

• T-cell receptor excision circles (TRECs); extrachromosomal DNA
episomes generated during V(D)J recombination
• not duplicated during mitosis
• identify newly generated naive T lymphocytes

• Quantification of TRECs
• assess engraftment of bona fide stem cells and
to monitor the persistence of immunity
• Decline by 10 years
• Possible that the SCID thymus is not able to
sustain active thymopoiesis for as long as a
normal thymus

Reconstitution of B- and NK-cell immunity
• ≥2 years to develop the engraftment of B cells
for SCID
• 6 of12 recipients of HLA-identical bone marrow,
and 21 of 76 patients treated by unconditioned T
cell-depleted haploidentical transplant had
evidence of donor-derived B lymphocytes
• 62 of 102 survivors were requiring intravenous
immunoglobulins
Buckley RH. Annu Rev Immunol 2004

Reconstitution of B- and NK-cell immunity
• Depend on the nature of the genetic defect
• B+ SCID, IL7RA gene defect usually develop
normal B-cell immunity after HSCT even if no
donor-derived B cells are present
• γc or JAK3 deficiency (both of which
compromise B-cell function) often remain
dependent on immunoglobulin substitution
• More limited data are available about
reconstitution of NK cell function

HSCT for immunodeficiencies
other than SCID

other than SCID
• Residual T cell-mediated immunity
• pre-transplant conditioning regimen is
required, even HLA-identical donor
• Alternative donors (MUDs and cord blood)
• Medical emergency
• Clinical history and quality of life

Survival following HSCT
• 23/79 HLA-identical transplant
• 13/79 by T cell-depleted haploidentical HSCT
• 43/79 by MUD HSCT
• The survival rates: 78.5%, 53.8%, 78.1%

other than SCID
HLA-identical Haploidentical MUD
Omenn’s syn 75% 41% 50%
MHC class II def 54% 32% -
WAS 87% 52% 71%
FHL 71% - 70%
Cartilage-hair
hypoplasia
Over all 50%
Purine nucleoside
phophorylate
Overall 50%
CD40L def Overall 46% at 25 yr of age

Wiskott–Aldrich syndrome
• Early as 1968, with partial success
• Full correction following HSCT first in 1978
• Good outcome in HLA-identical HSCT
• MUD HSCT was effective especially <5 years
• Cord blood transplantation increasingly

Cytotoxicity defects
• Familial hemophagocytic lymphohistiocytosis (FHL)
– a stable donor chimerism ≥20% is sufficient to provide
long-term remission
– genetic testing is strongly recommended before HSCT
from a sibling is attempted
• Chediak–Higashi syndrome
– Better results with HSCT from HLA-identical siblings or
MUDs
– 3 patients, all are alive and in full remission

other than SCID
• Poor outcome in Interferon-Ƴ receptor 1
deficiency, IPEX syndrome
(Immunodysregulation,
polyendocrinopathy, enteropathy, X-
linked)

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