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


Sources of hematopoietic stem cells for transplantation


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



Quality and kinetics of T-cell immune reconstitution

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

HSCT for immunodeficiencies

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% Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd


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


• Poor outcome in Interferon-Ƴ receptor 1

deficiency, IPEX syndrome

(Immunodysregulation,

polyendocrinopathy, enteropathy, X-

linked)

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Transplantation