GVHD Pathogenesis and Therapy
Tuesday, March 07, 2006
Exciting new advances in hematopoietic cell transplantation
biology have occurred in the past two decades. New methods of
transplantation (autologous and stem cell cord blood), more
specific reagents and methods to match donors and recipients, and
new conditioning regimens (radiation therapy and chemotherapy) to
prepare recipients for transplantation are being used. A wider
variety of individuals, including older patients, can undergo
transplantation. New concepts about graft versus host disease
(GVHD) and graft versus malignancy reactions have revolutionized
the field. However, GVHD continues to be a major complication of
hematopoietic cell transplantation, occurring in 30-80% of
GVHD and Dermatologists
The cutaneous manifestations and therapies that dermatologists
would encounter are our focus here. As our ability to prevent
severe GVHD improves, more patients may need only management of
their mild cutaneous GVHD. This could be done on an outpatient
basis by dermatologists, the recognized experts in skin care.
Why Does GVHD Occur? Who Is at Risk?
GVHD occurs when "the graft contains immunologically competent
cells, the recipient expresses tissue antigens that are not present
in the transplant donor, and the recipient is incapable of mounting
an effective response to destroy the transplanted
cells."1 Dendritic cells, T cells, natural killer (NK)
cells, macrophages, cytokines, and surface markers on immune cells
(major and minor histocompatibility antigens MHC and MiHC,
respectively) are the mediators of GVHD. The recipient is usually
immunocompromised by irradiation and chemotherapy (conditioning
The main risks for GVHD are:
- Donor-recipient gender mismatch
- Histocompatibility antigen mismatch
- Older age of recipient
- High numbers of T cells transfused from donor
- Recipient exposure to previous blood product transfusion
- Low concentrations of immunosuppressants in
In addition to GVHD, life-threatening infections due to
immunosuppression can also occur.
Histocompatibility Antigens and GVHD
The histocompatibility antigens are responsible for rejection of
tissue grafts between different strains of animals and different
individuals. Human major histocompatibility complex (MHC) genes
encode antigens, many of which involve T-cell activation. They are
designated MHC class I and class II and lie on the short arm of
chromosome 6, called the HLA (human leukocyte antigen) region. MHC
class I and class II antigens are usually typed by molecular
methods now. The average patient has a 20-30% chance of having an
HLA match within his or her immediate family because of close
Minor histocompatibility antigens (MiHC) are also important in
GVHD but are less well understood and characterized. Depending on
the degree of MHC and MiHC mismatch and the presence of certain
critical genetic differences in donor and recipient, GVHD can
The Targets of GVHD
The skin, liver, and mucosa are "barrier epithelia," which can
respond rapidly to external insults with inflammation. A plausible
hypothesis for GVHD is that conditioning with radiation therapy and
chemotherapy before transplantation damages tissue, causing release
of cytokines and chemokines and causing nonspecific inflammation in
the barrier epithelia. Host antigen-presenting cells in these sites
are activated, and then interact with donor lymphocytes brought to
the area by the inflammation. The donor lymphocytes proliferate and
trigger downstream events (more cytokine secretion, activation of
macrophages and NK cells). Damage to epithelia of skin, gut, and
liver follows via direct cytotoxic injury and via cytokines that
cause keratinocyte apoptosis. The specific molecules targeted in
GVHD are not known, but are assumed to be cell-surface molecules
unique to epithelial cells. Therefore, damage to skin results from
a combination of "cytokine storm," antigen-presenting cell
activation, and direct cytotoxic T-cell and NK-cell injury to
keratinocytes (satellite necrosis).3,4
Each individual may have a unique "cytokine phenotype" that
predisposes him or her to either severe or mild GVHD. These
cytokine phenotypes may be important markers in the future to
evaluate before transplantation.
Types of GVHD
Acute GVHD: Acute GVHD ("dermatitis, hepatitis, and enteritis"
representing injury to epithelia in the barrier organs by activated
immune cells) can occur within the first weeks after
transplantation. Skin is an early target. GVHD usually begins on
the palms, soles, ears, and oral mucosa as tender erythematous
macules, patches, and plaques that generally precede liver and
gastrointestinal involvement. Acute GVHD is graded by percentage of
total skin that is inflamed, amount of diarrhea per 24 hours, and
serum level of bilirubin. Cutaneous GVHD typically has interface
dermatitis with epidermal injury out of proportion to the
inflammation, which is minimal, suggesting the importance of
cytokines in acute GVHD.
Prophylaxis with cyclosporin A and methotrexate, and methyl
prednisone for approximately 2 weeks, is standard, with a
glucocorticoid taper if GVHD manifestations are resolving. Up to
80% of individuals require secondary therapies shown in Table
1.5 Extracorporeal photopheresis has also been used
|Therapies for GVHD13,14,15
|Polyclonal anti-thymocyte globulin (ATG)
|Glucocorticoids (5-20 mg/kg/day)
|Monoclonal Abs to cell-surface markers and cytokine
Chronic GVHD: Individuals with chronic GVHD
(persists or occurs de novo beyond 80-100 days post bone marrow
transplantation) have clinical symptoms resembling an overlap of
connective tissue diseases (such as lupus erythematosus, mixed
connective tissue disease, scleroderma, Sjogren syndrome, biliary
cirrhosis, and idiopathic pulmonary fibrosis). It occurs in
approximately 30-60% of patients.
- Limited chronic GVHD has mild involvement of skin, ocular,
oral, or vaginal mucosa and small changes in liver function
- Severe chronic GVHD has more extensive epithelial involvement:
serositis, hepatitis, biliary cirrhosis, severe gastrointestinal
injury, and bronchiolitis obliterans; alopecia and pigmentary
changes; increased susceptibility to skin cancers; and increased
susceptibility to cutaneous viral and fungal infections (herpes,
molluscum, candida, and opportunistic deep fungi).
Two types of chronic cutaneous GVHD can occur:
- Lichenoid GVHD (lupus-like): lichenoid papules resembling
lichen planus in flexural surfaces and white mucosal patches
- Sclerodermatous GVHD (scleroderma-like): firm fibrotic plaques
on skin, with esophageal dysmotility and joint contractures
Limited chronic GVHD typically does not require systemic
therapy. Early administration of long-term systemic glucocorticoids
and cyclosporin or tacrolimus has historically been the treatment
of severe chronic GVHD. Many of the immunomodulatory agents in
Table 1 are also useful in chronic GVHD. A significant number of
patients improve clinically with extracorporeal
photopheresis6,7 and PUVA. Artificial tears for ocular
dryness, pilocarpine for xerostomia, and nutritional supplements
for severe mucositis are also used for supportive care.
Anti-osteoporosis regimens help to decrease bone loss from
long-term corticosteroid therapy. New topical immunomodulatory
agents may be promising alternatives to systemic immunosuppression
if only skin is involved.
The Good and the Bad of GVHD
Graft versus malignancy/graft versus leukemia
reaction: Transplanted individuals with GVHD may have a
lower rate of relapse of their malignancy than individuals without
GVHD, because the donor lymphocytes attack not only host target
tissues but also residual host malignant cells. Also, relapsed
individuals can return to remission after another infusion of donor
lymphocytes. Therefore current management strategies for GVHD are
to maintain a delicate balance with less intensive and
non-myeloblative conditioning and sufficient immunosuppression to
maintain the engraftment and hematopoiesis in order to produce the
graft versus malignancy effect.
This strategy allows transplantation of older individuals
(>50 years) who were not previously eligible for
Methods of Transplantation and GVHD
Allogeneic bone marrow transplantation
(transplantation of bone marrow from one genetically unique
individual to another unique individual): The typical
transplantation scenario is bone marrow from one sibling with close
MHC identity to another sibling. However, a perfect HLA match does
not prevent GVHD because the MiHC can differ between siblings.
There are also genetically determined polymorphisms of genes for
cytokines, chemokines, and molecules of the innate immune system
that recognize bacteria and viruses that have also been shown to be
important. This area of investigation holds great promise for the
future. Better methods of genetic and immunologic matching will
continue to improve survival and decrease morbidity due to severe
Hematopoietic stem cell transplantation (HSC):
HSC is a great improvement because the transplant infusion material
is enriched for CD34-positive hematopoietic stem cells, allowing
transplantation of fewer cells and more rapid recovery of the
recipient immune system. However, the risk for GHVD is higher with
stem cell transplantation.10
Cord blood transplantation: Immune cells in
neonatal cord blood from placenta are also used for
transplantation. Because the neonatal immune system is immature
(naive), it is possible to transplant across large disparities in
HLA antigens without causing severe GVHD, thereby enlarging the
numbers of potential donors for transplantation. The disadvantage
of cord blood transplantation is that the transplanted immune
system remains immature for a long time (up to 18 months),
increasing susceptibility to fungal and viral infections. Also,
obtaining enough cord blood to transplant an adult is a limiting
GVHD is a potentially devastating consequence of hematopoietic
cell transplantation that is immunologically mediated. Several
variant forms exist (acute, chronic lichenoid, chronic
sclerodermatous). GVHD results from attack of transplanted donor
lymphocytes on host tissues when histocompatibility and immunologic
differences exist between donor and recipient. Skin is a major
early target, along with gut and liver.
Graft versus malignancy is a useful phenomenon that is being
utilized to enhance survival of transplanted individuals. In the
past, therapy has been with potent nonspecific immunosuppressants.
More recently, exciting new more focused therapies
(immunomodulatory molecules and antibodies to immune cell markers,
PUVA, extracorporeal photopheresis) have been developed and are
increasingly useful to enhance survival and increase quality of
life after transplantation.
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- Penas PF, Jones-Caballero M, Aragues M, et al. Sclerodermatous
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- Furlong T, Leisenring W, Storb R, et al. Psoralen and
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- Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic
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- Isoyama K, Ohnuma K, Kato K, et al. Cord blood transplantation
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