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Research Updates

Anita C. Gilliam, MD, PhD

GVHD Pathogenesis and Therapy

Anita Gilliam

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 recipients.

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 regimen).

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 recipient2

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 genetic relationships.

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 occur.

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 successfully.6,7

Table 1.


Therapies for GVHD13,14,15
Polyclonal anti-thymocyte globulin (ATG)
Glucocorticoids (5-20 mg/kg/day)
Tacrolimus, sirolimus
Mycophenolic acid
Monoclonal Abs to cell-surface markers and cytokine receptors

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 tests.
  • 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 (approximately 15%)8

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 transplantation.

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 GVHD.9

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 factor.11,12

Conclusions

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.

References

  1. Billingham, RE. The biology of graft versus host disease. Harvey Lectures. 1966;62:21.
  2. Dean RM, Bishop MR. Graft-versus-host disease: emerging concepts in prevention and therapy. Curr Hematol Rep. 2003;2(4):287-94.
  3. Ferrara, JL. Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. J Hematother Stem Cell Res. 2000:9(3):299-306.
  4. Teshima T, Ferrara JL. Understanding the alloresponse: new approaches to graft-versus-host disease prevention. Semin Hematol. 2002;39(1):15-22.
  5. Carpenter PA, Sanders JE. Steroid-refractory graft-vs-host disease: past, present and future. Pediatr Transplant. 2003;7 Suppl 3:19-31.
  6. Greinix HT, Volc-Platzer B, Rabitsch W, et al. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood. 1998;92(9):3098-104.
  7. Zic JA, Miller JL, Stricklin GP, et al. The North American experience with photopheresis. Ther Apher. 1999;3(1):50-62.
  8. Penas PF, Jones-Caballero M, Aragues M, et al. Sclerodermatous graft-versus-host disease: clinical and pathological study of 17 patients. Arch Dermatol. 2002;138(7):924-34.
  9. Furlong T, Leisenring W, Storb R, et al. Psoralen and ultraviolet A irradiation (PUVA) as therapy for steroid-resistant cutaneous acute graft-versus-host disease. Biol Blood Marrow Transplant. 2002;8(4):206-12.
  10. Anagnostopoulos A, Giralt S. Critical review on non-myeloablative stem cell transplantation (NST). Crit Rev Onc Hematol. 2002;44(2):175-90.
  11. Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med. 2001;344(24):1815-22.
  12. Isoyama K, Ohnuma K, Kato K, et al. Cord blood transplantation from unrelated donors: a preliminary report from the Japanese Cord Blood Bank Network. Leuk Lymphoma. 2003;44(3):429-38.
  13. Bruner RJ, Farag SS. Monoclonal antibodies for the prevention and treatment of graft-versus-host disease. Semin Oncol. 2003;30(4):509-19.
  14. Vogelsang GB, Lee L, Bensen-Kennedy DM. Pathogenesis and treatment of graft-versus-host disease after bone marrow transplant. Annu Rev Med. 2003;54:29-52.
  15. Davies JK, Lowdell MW. New advances in acute graft versus host disease prophylaxis. Transfus Med. 2003;1(6)3:387-97.
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