Graft Versus Host Disease 

  • Author: Romeo A Mandanas, MD, FACP; Chief Editor: Mary C Mancini, MD, PhD   more...
 
Updated: Oct 28, 2010
 

Background

Barnes and Loutit first described (in mice) what is now known as graft versus host disease (GVHD) as a syndrome called secondary disease to differentiate it from primary disease of radiation sickness. Mice that were given allogeneic spleen cells after irradiation developed fatal secondary disease (skin abnormalities and diarrhea), which was a result of introducing immunologically competent cells into an immunoincompetent host.

Human GVHD occurs after allogeneic stem-cell transplantation, with features similar to those observed in animal studies. Acute GVHD describes a distinctive syndrome of dermatitis, hepatitis, and enteritis developing within 100 days of allogeneic hematopoietic-cell transplantation (HCT). Chronic GVHD describes a more diverse syndrome developing after day 100.

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Pathophysiology

Several criteria, as first described by Billingham in 1966,[1] are traditionally required to diagnose GVHD, including the following:

  • The graft must contain immunologically competent cells.
  • The host must possess important transplantation alloantigens that are lacking in the donor graft so that the host appears foreign to the graft and can therefore stimulate it antigenically.
  • The host itself must be incapable of mounting an effective immunologic reaction against the graft, or it must at least allow for sufficient time for the latter to manifest its immunologic capabilities, ie, it must have the security of tenure.

Certain patient groups are at risk for GVHD, as outlined in Table 1.

Table 1. Procedures Associated with a High Risk of GVHD* (Open Table in a new window)

ProcedureGroups at High Risk
Allogeneic HCTPatients receiving no GVHD prophylaxis



Older patients



Recipients of HLA-nonidentical stem cells



Recipients of graft from allosensitized donors



Recipients of grafts from unrelated donors



Solid-organ transplantation (organs containing lymphoid tissue)Recipients of small-bowel transplants
Transfusion of unirradiated blood productsNeonates and fetuses



Patients with congenital immunodeficiency syndromes



Patients receiving immunosuppressive chemoradiotherapy



Patients receiving directed blood donations from partially HLA-identical, HLA-homologous donors



*Modified from Ferrara and Deeg, 1991.[2]

HLA = Human leukocyte antigen.

Current understanding of the biology of GVHD includes the occurrence of autologous GVHD and transfusion-associated GVHD. The former suggests that inappropriate recognition of host self-antigens may occur, and the latter is an example of GVHD in an individual who is immunocompetent (see image below).

Autologous graft versus host disease (GVHD) involvAutologous graft versus host disease (GVHD) involving the skin of a patient's arm appeared shortly after signs of engraftment appeared. The patient had undergone autologous peripheral blood stem-cell transplantation to treat ovarian cancer. Courtesy of Romeo A. Mandanas, MD, FACP.

GVHD is an immune-mediated disease resulting from a complex interaction between donor and recipient adaptive immunity.[3] The main effectors are donor T cells, which are activated in the presence of co-stimulatory molecules by a storm of proinflammatory cytokines[4] (see image below). The successful use of B cell targeted therapy like rituximab in chronic GVHD has sparked an interest in defining the role of B cells in the pathophysiology of GVHD.[5]

Interactive factors involved in the pathogenesis oInteractive factors involved in the pathogenesis of graft versus host disease (GVHD.) Courtesy of Romeo A. Mandanas, MD, FACP.

Chronic GVHD is a syndrome that mimics the autoimmune diseases. Donor T cells play an important role in its development, but humoral immunity is also implicated. The targets of attack may include host non-HLA antigens like minor histocompatibility antigens. In some studies, host dendritic cells may also be at play. A close relationship exists between the development of chronic GVHD and a helpful graft-versus-tumor/leukemia effect.[6]

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Epidemiology

Frequency

United States

Autologous GVHD occasionally occurs after autologous or syngeneic HCT (7-10%). Tissue damage caused by high-dose chemotherapy or secondary cytokine production may expose cryptic self-antigens, which the immune system may newly recognize only after HCT. Mild and usually self-limited episodes of dermal GVHD or even hepatic and GI abnormalities have been described. GVHD-like symptoms and findings can also be induced in autologous recipients after the administration (and withdrawal) of cyclosporin (CSP) and interleukin (IL)-2.[7]

Transfusion-associated GVHD occurs 4-30 days after transfusion and resembles hyperacute GVHD after allogeneic HCT. Marrow aplasia is a frequent and often fatal complication. This serious complication of transfusion can be prevented by irradiating blood products with at least 2500 cGy before transfusion in individuals at risk. In Japan (where inbred populations share common haplotypes), marrow aplasia is estimated to occur in 1 in 500 open-heart operations in individuals who are immunocompetent.

The occurrence of acute GVHD in patients who receive marrow from HLA-identical siblings varies widely depending on several recognized risk factors. About 19-66% of recipients are affected, depending on their age, on donor-recipient sex matching, and on donor parity. The incidence of GVHD increases with HLA-nonidentical marrow donors who are related or in HLA-matched unrelated donors, with rates of 70-90%.[8]

Chronic GVHD is observed in 33% of HLA-identical sibling transplantations, in 49% of HLA-identical related transplantations, in 64% of matched unrelated donor transplantations. The rate could be as high as 80% in 1-antigen HLA-nonidentical unrelated transplantations.[6]

The source of donor graft affects the incidence of GVHD. Although acute GVHD does not differ significantly among recipients of HLA-identical sibling bone marrow (BM) versus peripheral blood stem cells (PBSC), the cumulative incidence of chronic GVHD (and extensive GVHD) is higher in those who received PBSC (73% vs. 55%).[9, 10] Cumulative incidence of Grades III-IV acute and extensive chronic GVHD is much lesser in unrelated cord blood recipients than in either recipients of HLA-identical sibling BM or PBSC transplants.[11]

Mortality/Morbidity

  • The overall grade of acute GVHD is predictive of the patient's outcome, with the highest rates of mortality in those with grade IV, or severe, GVHD.
  • The response to treatment is also predictive of outcomes in GVHD of grades II-IV. Patients with no response or with progression have a mortality rate as high as 75% compared with 20-25% in those with a complete response.[8]
  • In chronic GVHD, mortality rates are increased in patients with extensive disease, progressive onset, thrombocytopenia, and HLA-nonidentical marrow donors. The overall survival rate is 42%, but patients with progressive onset of chronic GVHD have a survival rate of 10%.[12]
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Contributor Information and Disclosures
Author

Romeo A Mandanas, MD, FACP  Research Site Leader, Integris Cancer Institute of Oklahoma

Romeo A Mandanas, MD, FACP, is a member of the following medical societies: American College of Physicians, American Medical Association, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Oklahoma State Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Antoni Ribas, MD  Assistant Professor of Medicine, Division of Hematology-Oncology, University of California at Los Angeles Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Marcel E Conrad, MD  Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: No financial interests None None

Chief Editor

Mary C Mancini, MD, PhD  Professor and Chief, Cardiothoracic Surgery, Department of Surgery, Louisiana State University Health Sciences Center-Shreveport

Mary C Mancini, MD, PhD is a member of the following medical societies: American Association for Thoracic Surgery, American College of Surgeons, American Surgical Association, Phi Beta Kappa, Society of Thoracic Surgeons, and Southern Surgical Association

Disclosure: Nothing to disclose.

References

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  29. Mollee P, Morton AJ, Irving I, et al. Combination therapy with tacrolimus and anti-thymocyte globulin for the treatment of steroid-resistant acute graft-versus-host disease developing during cyclosporine prophylaxis. Br J Haematol. Apr 2001;113(1):217-23. [Medline].

  30. Lopez F, Parker P, Nademanee A, Rodriguez R, Al-Kadhimi Z, Bhatia R. Efficacy of mycophenolate mofetil in the treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant. Apr 2005;11(4):307-13. [Medline].

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Autologous graft versus host disease (GVHD) involving the skin of a patient's arm appeared shortly after signs of engraftment appeared. The patient had undergone autologous peripheral blood stem-cell transplantation to treat ovarian cancer. Courtesy of Romeo A. Mandanas, MD, FACP.
Acute graft versus host disease (GVHD) involving desquamating skin lesions in a patient after allogeneic bone marrow transplantation for myelodysplasia. Courtesy of Romeo A. Mandanas, MD, FACP.
Oral mucosal changes in a patient with chronic graft versus host disease (GVHD). Note the skin discoloration (vitiligo), which can be a result of GVHD. Courtesy of Romeo A. Mandanas, MD, FACP.
Interactive factors involved in the pathogenesis of graft versus host disease (GVHD.) Courtesy of Romeo A. Mandanas, MD, FACP.
This boy developed stage III skin involvement with acute graft versus host disease (GVHD) despite of receiving prophylaxis with cyclosporin A. The donor was his HLA-matched sister; the sex disparity increased the risk for acute GVHD. Courtesy of Mustafa S. Suterwala, MD.
Same boy as in previous image progressed to grade IV graft versus host disease (GVHD). High-dose cyclosporin A and methylprednisolone had been administered intravenously. He later died from chronic pulmonary disease due to chronic GVHD. Courtesy of Mustafa S. Suterwala, MD.
Acute graft versus host disease (GVHD). Hematoxylin and eosin–stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. Moderate superficial dermal and perivascular lymphocytic infiltrate are also observed. Courtesy of Melanie K. Kuechler, MD.
Table 1. Procedures Associated with a High Risk of GVHD*
ProcedureGroups at High Risk
Allogeneic HCTPatients receiving no GVHD prophylaxis



Older patients



Recipients of HLA-nonidentical stem cells



Recipients of graft from allosensitized donors



Recipients of grafts from unrelated donors



Solid-organ transplantation (organs containing lymphoid tissue)Recipients of small-bowel transplants
Transfusion of unirradiated blood productsNeonates and fetuses



Patients with congenital immunodeficiency syndromes



Patients receiving immunosuppressive chemoradiotherapy



Patients receiving directed blood donations from partially HLA-identical, HLA-homologous donors



Table 2. Clinical Staging of Acute GVHD
StageSkin FindingsLiver Findings (Bilirubin level, mg/dL)Gut Findings
+Maculopapular rash on < 25% of body surface2-3Diarrhea 500-1000 mL/d or persistent nausea
++Maculopapular rash on 25-50% of body surface3-6Diarrhea 1000-1500 mL/d
+++Generalized erythroderma6-15Diarrhea >1500 mL/d
++++Desquamation and bullae>15Pain with or without ileus
Table 3. Clinical Grading of Acute GVHD
Overall GradeStage
SkinLiverGutFunctional Impairment
0 (None)0000
I (Mild)+ to ++000
II (Moderate)+ to ++++++
III (Severe)++ to +++++ to +++++ to +++++
IV (Life-threatening)++ to ++++++ to ++++++ to +++++++
Table 4. Clinicopathologic Classification of Chronic GVHD
ClassificationClinicopathology
LimitedLocalized skin involvement and/or hepatic dysfunction due to chronic GVHD
ExtensiveGeneralized skin involvement or localized skin involvement and/or hepatic dysfunction due to chronic GVHD, plus 1 of the following:



- Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis



- Involvement of the eye (Schirmer test with < 5-mm wetting)



- Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy



- Involvement of any other target organ



Table 5. Screening Studies for GVHD by Organ or System
Organ or SystemClinical FindingsScreening Studies
SkinDyspigmentation, xerosis, erythema, scleroderma, onychodystrophy, alopeciaSkin biopsy with a 3-mm punch-biopsy sample from the back and forearm areas
MouthLichen planus, xerostomiaOral biopsy with sample from lower lip
EyesSicca, keratitisSchirmer test
LiverJaundiceAlkaline phosphatase, AST, bilirubin determinations
LungsObstructive and/or restrictive lung diseasePulmonary function studies, arterial blood gas analysis
VaginaSicca, atrophyGynecologic evaluation
GI (nutrition)Protein and calorie deficiencyWeight, measurement of muscle and/or fat stores
Multiple (clinical performance)Contractures, debilityDetermination of Karnofsky score and Lansky play index
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