GRAFT VS HOST DISEASE

Andani Eka Putra

Pusat Diagnostik dan Riset Penyakit Infeksi
Bagian Mikrobiologi FK. Unand
 POINTS TO BE DISCUSSED

Immunogenetics – basic facts

Histocompatibility antigens and their role in
transplantation
Types of grafts, including fetus
Mechanisms of graft rejection
The tempo of rejection
Prevention of rejection
Graft versus host reaction
Infection
MAJOR HISTOCOMPATIBILITY
COMPLEX (MHC)
Is located on short arm of chromosome 6
It includes 3 regions: class Ia (loci A, B, C)
class Ib (loci E, F, G, H), class II (loci DR, DQ,
DP) and class III
Genes of class Ia and class II are highly
polymorphic, while those of class Ib and class
III are not
Polymorphism means occurence of several
allelles ie.genes encoding various MHC
antigens located at the same locus
 MAJOR HISTOCOMPATIBILITY
ANTIGENS

Histocompatibility antigens are cell surface

expressed on all cells (class I) and on APC,
B cells, monocytes/macrophages (class II)
They are targets for rejection
They are inherited from both parents as MHC
haplotypes and are co-dominantly expressed
 MINOR HISTOCOMPATIBILITY
ANTIGENS
They also participate in rejection but to lesser
degree
Disparity of several minor antigens may result
in rejection, even when MHC antigens are
concordant between donor and recipient
They include blood group antigens, tissue
and organ antigens, normal cellular
constituents
They are peptides derived from polymorphic
cellular proteins bound to MHC class I molecules
 TYPES OF GRAFTS

Autologous graft (autograft) – in the same

individual: from one site to another one
Isogenic (isograft) – between genetically
identical individuals
Allogeneic (allograft or homograft) – between
different members of the same species
Xenogeneic (xenograft) – between mmbers of
different species
 MECHANISMS OF REJECTION
Depend on disparity of genetic background
between donor and recipient
T cells are critical in graft rejection
Rejection responses in molecular terms, are due
to TCR-MHC interaction
Graft and host MHC molecules present different
peptides
Different MHC molecules have different peptide-
binding grooves
T lymphocytes can directly recognize and
respond to foreign MHC molecules
 ALLOREACTIVE CELLS ARE SO
COMMON, BECAUSE:

Foreign MHC molecules differ from self MHC at

multiple different aminoacid residues, each of
which may produce determinant recognized by
a different cross-reactive T cell clone
Thus, each foreign MHC molecule is recognized
by multiple clones of T cells
2% of host T cells are capable recognizing and
responding to a single MHC foreign molecule
 TEMPO OF REJECTION
Hyperacute rejection
antibodies to HLA and ABO blood group system
(hours or first days)
Acute rejection
T cells (days or weeks)
Chronic rejection
various mechanisms: cell-mediated, deposition
of antibodies or antigen antibody complexes with
subsequent obliteration of blood vessels and
interstitial fibrosis (months or years)
THE MODE OF ACTION OF ANTIBODIES
IN TRANSPLANT REJECTION

By damage of endothelial cells due to activation

of complement
By induction of ADCC reaction
Through intensification of inflammatory reaction
by the release of complement components
(C3a, C5a)
By activation of clotting system
 VARIABLES DETERMINING
TRANSPLANT OUTCOME

Donor-host antigenic disparity

Strength of host anti donor response
Immunosuppressive regimen
The condition of the allograft
Primary disease of the host
 PATHOGENESIS OF CHRONIC
REJECTION
Is the result of organ damage by
immunologic and non-immunologic factors

Initially – the minor damage and activation

of endothelium by cytotoxic T cells and
antibodies
 PATHOGENESIS OF CHRONIC
REJECTION -2
Production by endothelial cells biologically active
mediators (PDGF, PAF, TNF, thromboxans etc.)

Secretion of cytokines by infiltrating lymphocytes

Mitogenic effect on myocytes and fibroblasts

results in cell proliferation and fibrosis
 CHRONIC REJECTION IS MORE
FREQUENT WHEN:
Were previous episodes of acute rejection

There is a low number of compatible HLA

antigens with recipient

Patient on inadequate immunosuppression

Recipient is hypertonic
>>>
 CHRONIC REJECTION IS
MORE FREQUENT WHEN:

<<<
In the case of cytomegaly virus infection
The period of organ storage was too long
Patient is heavy smoker and/or is hyperlipidemic
Organ mass is unproportionally small as
compared to body mass
 MODERN IMMUNOSUPPRESSIVE
THERAPY
Cyclosporin (CsA), Tacrolimus (FK-506) – inhibit IL-2
production by T cells calcineurin antagonist

Sirolimus (rapamycin) – inhibits signals transmitted by

IL-2 binding to IL-2R (antiproliferating effect)

Azathioprine – reduces numbers and function both, T

and B cells, by inhibition of purine metabolism
 MODERN IMMUNOSUPPRESSIVE
THERAPY -2

Mycophenolate mofetil (MMF) – inhibits DNA

synthesis and protein glycosylation, supresses
expression of CD25, -71, -154, -28.

Anti-IL-2 monoclonal antibodies

FTY 720 – dramatic effect on lymphocyte

migration
GRAFT VERSUS HOST DISEASE (GVH)
Is common complication in recipients of
bone marrow transplants

Is due to the presence of alloreactive T

cells in the graft

It results in severe tissue damage,

particularly to the skin and intestine
GRAFT VERSUS HOST DISEASE (GVH)

It may be avoided by careful typing,

removal of mature T cells from the graft
and by immunosuppressive drugs

It is manifested by marked rise of several

cytokines in patient’s serum (IFN-, TNF,
IL-1, IL-2, IL-4)
RISK FACTORS IN FORMATION OF GVH

Acute GVH Chronic GVH

Previous pregnancies in Aging of donor and
female donor recipient
High T cell number in Donor’s leukocyte
marrow transfusion
HLA disparity Previous acute GVH
Transplant from female to High dosage radiation
male Transplant from female to
Low immunosuppression man
Herpes virus infection HLA disparity
 GRAFT VERSUS LEUKEMIA (GVL)

It is reaction of donor’s lymphocytes from bone

marrow graft versus antigens on tumor cells
It is postulated that apart from GVH, there exists
independent GVL component
GVL is due to T cells and NK cells
Relapses of leukemia are rarer in those patients,
who experienced GVH after marrow transplant
GVL may be enhanced by transfusion of
lymphocytes obtained from marrow donors +IL-2
 The fetus is allograft that is tolerated
repeatedly
Fetus carries paternal MHC and minor H antigens that
differ from those of mother
Still, fetus is an allograft that is not rejected
Women who born several children make antibodies
directed at father’s MHC proteins

Possible explanations of this puzzle:

 Lack of classic MHC antigens on cells of trophoblast cells (TC)
(protection from maternal T cells)
 Presence of HLA-G antigens on TC (protection from NK cells)
 Secretion of suppresive cytokines by TC and uterine epithelium
(TGF-beta, IL-10, IL-4)
 PERSPECTIVES OF XENOGENEIC
GRAFTS
Potential advantage due to larger
accessibility of animal organs

Monkeys are apparently the most suitable

donors, but dangerous because of
potential risk of retrovirus transfer within
graft
 PERSPECTIVES OF XENOGENEIC
GRAFTS - 2
Pigs are now considered because of
similar sizes of organs and erythrocytes to
human ones

The major obstacle – presence in man

(1%) of natural antibodies vs. Gal
(galactose--1,3-galactose) causing
hyperacute rejection
Infection after SCT
 Infection after SCT
Infection is the most common cause of
non-relapse death
Risk increases with:
previous treatment
history of infection (especially fungal)
tissue injury (especially mucositis)
duration of neutropenia
GVHD and treatment thereof (prednisone)
mismatched/unrelated vs. matched/related
 Infection of SCT patients
Phase I - first month
Host immune system defect
skin, mucous membrane, neutropenia
Pathogens
staph epidermidis
facultative gram neg bacilli
oropharyngeal streptococci
all candida, aspergillus
respiratory and enteric viruses
 Infection of SCT patients
Phase II - 30 to 100 days
Host immune system defect
Impaired cellular immunity, GVHD
Pathogens
CMV
all candida, aspergillus
staph epidermidis
respiratory and enteric viruses
EBV (for T cell depleted SCT)
 Infection of SCT patients
Phase III - > 100 days
Host immune system defect
Impaired cellular and humoral immunity
Pathogens
CMV
Encapsulated bacteria
Aspergillus species
varicella-zoster, EBV
PCP, Toxoplasma
 Invasive Fungal Infection
Incidence 10 - 20%
Mortality 70%
Autopsy 10 - 30%
Candida sp.
Krusei, glabrata
Aspergillus sp.
Diagnosis difficult
Risk Factors for Invasive Fungal
Infection
Strong Association Weak Association
Acute GVHD Splenectormy
ATG treatment CMV Pos
Age TBI
Fungal colonization low BM dose
Long neutropenia HSV positive donor
Dx: AML
HLA mismatched
Available at

http://www.cdc.gov/m
mwr/
preview/mmwrhtml/
rr4910a1.htm
Systemic Fungal Infections Diagnosed
in HSCT Recipients, by Prophylaxis
Used Yes No Total
Fluconazole 5 (3%) 174 179
Placebo 28 (16%)149 177
Total 33 323 356

OR = 0.15, 95% C.I. (0.05, 0.42), P < 0.001

Goodman JL, et al. N Engl J Med 1992;326(13):845-851.
 Ventilation Recommendations
Allogeneic HSCT recipients
• Rooms with >12 air exchanges/hour [AIII]
• Point-of-use high efficiency (>99%) particulate
air (HEPA) filters that are capable of removing
particles >0.3 µm in diameter [AIII]

Autologous HSCT recipients

• Use of HEPA-filtered rooms should be
considered for autologous HSCT recipients if
they develop prolonged neutropenia [CIII]
 Positive Room Air Pressure
• Hospital rooms for HSCT recipients should have
positive room air pressure
• HSCT units should maintain consistent pressure
differentials between the patient’s room and the
hallway or anteroom at >2.5 Pascals or 0.01 inch
by water gauge [BIII]
 Equipment and Supplies
• All HSCT units should sterilize or disinfect and
maintain equipment and devices using only FDA-
or EPA-registered compounds as directed by
established guidelines [AIII]
• HSCT units should monitor opened and unopened
wound dressing supplies [BIII]
• Monitoring should consist of discarding all bandages
and wound dressings that are out of date, have
damaged packaging, or are visually contaminated by
construction debris or moisture [BIII]
 HSCT Hospital Surveillance
NO
• Routine bacterial and fungal patient surveillance
cultures [DII]

YES
• Routine fungal environmental surveillance
cultures [CIII]
• Routine surveillance for the number of
aspergillosis cases in HSCT recipients [BIII]
 Viral Infections after SCT
Common
CMV, HSV, VZV Prophylaxis/Treatment
Less common Acyclovir
Adenovirus, influenza A, Ganciclovir
parainfluenza, RSV, Foscarnet
Rhinovirus Avoidance
Rare Possible Treatments
Rotavirus, Coxsackie, RSV Ig, ribavirin
polyoma virus neuraminidase inhibitor,
rimantadine
 Community-Acquired Respiratory Virus
Infections After Marrow Transplant:
Fred Hutchinson Cancer Research Center (1990-1996)
Respiratory syncytial virus 44 (35%)
Parainfluenza 38 (30%)
Type 1 18
Type 2 4
Type 3 16
Rhinovirus 31 (25%)
Influenza 14 (11%)
Type A 12
Type B 2
Bowden R. Am J Med 1997;102(3A):27-30.
 Respiratory Syncytial Virus Infection in
Bone Marrow Transplant Patients
Fred Hutchinson Cancer Research Center,1990
9
Number of patients diagnosed

8
7
6
5
4
3
2
1
0
2 4 6 8 10 12 14 16
January February March April
Week
Harrington et al. J Infect Dis 1992;165:987-
 1991 Community Influenza Outbreak
Houston, TX
27% of 15 HSCT outpatients and 29% of 28 HSCT
inpatients with acute respiratory infections had
documented influenza - mortality 17%.
75% of all HSCT influenza cases during this
outbreak were associated with pneumonia.
Risk factors for severe influenza disease include
infection early after transplant just before
engraftment of chronic GVHD.
Many acquired the infection while hospitalized
Whimbey E. Bone Marrow Transplant 1994;13:437-40.
 Viral Shedding for CRV Infections
in HSCT Recipients

Duration Infection
up to 4 months influenza
up to 2 years adenovirus
up to 22 days RSV

Note: RSV viral shedding has been reported to

last 112 days in a child with SCID.
 URI Recommendations
HCWs and visitors with URI symptoms should be
restricted from contact with HSCT recipients and
candidates under-going conditioning therapy to
minimize the risk for CRV transmission (AIII).

Visitors with URI symptoms should be asked to

defer their visit to the HSCT center until their
URI symptoms resolve (BIII).

All HCWs with URI symptoms should be restricted

from patient contact and reassigned to non-
patient care duties until their symptoms resolve
(BIII).
Thank you for your attention