Cutaneous graft-versus-host disease

Graft-versus-host disease (GvHD) includes inflammatory and/or fibrosing manifestations that may arise at various times after transplantation of any organ containing lymphoid cells. For the dermatologist, the importance of GvHD is real and current. Indeed, because it has become easier to perform bone marrow transplantation (EMT), the indications of BMT have become broader, making follow-up of patients receiving grafts a widespread practice. Nonetheless, GvHD remains a frequent complication of BMT and its principal target organ is the skin. Furthermore, recent innovations, such as grafting of umbilical cord blood and the mobilization of peripheral blood progenitor cells, will be the source of new questions concerning the development of GvHD under these conditions. Finally, because of its analogies with other spontaneous idiopathic skin diseases, GvHD constitutes a model that may lead to a better understanding of the pathophysiological features of these diseases. In this review, the cutaneous aspects of GvHD are emphasized.     

Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines

The influence of bone marrow transplantation (BMT) conditioning regimens on the incidence and severity of graft-versus-host disease (GVHD) has been suggested in clinical BMT. Using murine BMT models, we show here an increase in GVHD severity in several donor-recipient strain combinations after intensification of the conditioning regimen by increasing the total body irradiation (TBI) dose from 900 cGy to 1,300 cGy. Increased GVHD was mediated by systemic increases in tumor necrosis factor alpha (TNF alpha). Histologic analysis of gastrointestinal tracts showed synergistic damage by increased TBI and allogeneic donor cells that permitted increased translocation of lipopolysacharide (LPS) into the systemic circulation. In vitro, LPS triggered excess TNF alpha from macrophages primed by the GVH reaction. In addition, macrophages isolated within 4 hours of conditioning were primed in proportion to the TBI dose itself to secrete TNF alpha. Thus, the higher TBI dose increased macrophage priming and increased gut damage after allogeneic BMT, causing higher systemic levels of inflammatory cytokines and subsequent severe GVHD. These data highlight the importance of conditioning in GVHD pathophysiology and suggest that interventions to prevent LPS stimulation of primed macrophages may limit the severity of GVHD after intensive conditioning for allogeneic BMT.     

A thymic hormone protects mice from enteropathy during acute graft-versus-host disease

We have previously reported that a nonapeptide thymic hormone, facteur thymique serique (FTS), is involved in the differentiation and activation of intestinal intraepithelial lymphocytes (i-IEL) in mice. In this study, we examined the effect of FTS treatment on enteropathy in a murine model for acute graft-vs.-host disease (GVHD) induced by injection of parental C57BL/6 splenocytes into unirradiated (C57BL/6 x DBA/2) F1 hybrids. FTS treatment significantly protected mice from developing acute GVHD as assessed by mortality rate, splenomegaly and enteropathy. The infiltration of donor-derived TCR alpha beta i-IEL bearing CD8 alpha beta was significantly inhibited in the small intestine of FTS-treated mice, and the frequencies of apoptosis of crypt cells in the intestinal mucosa were decreased in these mice during acute GVHD. These results suggest that FTS treatment contributes to protection against enteropathy of acute GVHD. Thus, FTS may provide a useful approach to control acute GVHD after blood transfusion or bone marrow transplantation.     

Phenotypic analysis of donor cells infiltrating the small intestinal epithelium and spleen during graft-versus-host disease

A pyriform sinus fistula can cause acute thyroiditis or recurrent infection in the neck. This fistula is believed to be a remnant of the branchial apparatus, although its origin has yet to be pinpointed. The spatial distribution of C cells in the thyroid gland was mapped by immunohistologic method in four patients with a pyriform sinus fistula. The C cells were identified immunohistologically with anticalcitonin antibody. The stained calcitonin-positive cells also crossreacted with the antibodies to carcinoembryonic antigen, chromogranin A, and neuron-specific enolase. The C cells were mainly distributed near the end of the fistula, and in three patients their concentration per unit volume of thyroid tissue was found to be inversely proportional to the distance from the end of the fistulas. Comparison of distant locations of the left-sided thyroid lobe in patients and the same region in control subjects showed a similar number of C cells. Thus this limited distribution of C cells suggested that the pyriform sinus fistula was either a remnant of the ultimobranchial body, the result of disturbed migration of the C cell in the fetus, or both.     

Chronic graft-versus-host disease treated with UVB phototherapy

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic bone marrow transplantation. Immunosuppressive treatment regimens carry the potential of causing severe morbidity and mortality, so that additional modes of therapy with fewer side-effects are clearly needed. Five cGVHD patients (sclerodermoid cGVHD in two patients, lichenoid cGVHD in one patient and intraoral cGVHD in two patients), who had not responded to standard immunosuppressive drugs, were treated with adjuvant UVB phototherapy. The patient with lichenoid cGVHD experienced complete clearing of cutaneous lesions, whereas both patients with sclerodermoid cGVHD experienced significant relief of pruritus, but showed no change of the sclerodermoid skin lesions. Intraoral lesions cleared in one patient. The effects of UVB phototherapy were furthermore documented by measurement of skin viscoelasticity and mouth opening. No side-effects were encountered. This preliminary study suggests that UVB phototherapy is useful as an adjuvant therapeutic modality in intraoral and cutaneous lichenoid cGVHD.     

Role of CD28 in acute graft-versus-host disease

Because CD28-mediated T-cell costimulation has a pivotal role in the initiation and maintenance of T-cell responses, we tested the hypothesis that CD28 is critical for the development of graft-versus-host disease (GVHD). We compared the in vivo effects of CD28(-/-) T cells transplanted from B6 donor with the CD28 gene deleted by homologous recombination with those of CD28(+/+) T cells transplanted from wild-type C57BL/6 (B6) donor. Fifty million CD28(-/-) or CD28(+/+) splenocytes from B6 mice were transplanted into unirradiated (B6 x DBA/2)F1 (BDF1) recipients. Unlike CD28(+/+), CD28(-/-) T cells from B6 mice had lower levels of proliferation and interleukin-2 production, had a limited ability to generate cytotoxic T lymphocytes against the recipient, and did not induce immune deficiency, despite survival in the recipient for at least 28 days. The ability to prevent rejection was reduced by the absence of CD28, because as many as 1.0 x 10(7) CD28(-/-) CD8(+) cells were needed to prevent rejection of major histocompatibility complex (MHC) class-I incompatible marrow in sublethally irradiated (550 cGy) bm1 recipients, whereas 8.0 x 10(5) CD28(+/+) CD8(+) T cells were sufficient to produce a similar effect, indicating that CD28 on donor CD8(+) cells helps to eliminate host immunity. Two million CD4(+) CD28(-/-) or CD28(+/+) T cells were transplanted into sublethally irradiated (750 cGy), MHC class-II incompatible (B6 x bm12)F1 recipients. With CD28(-/-) cells, 44% of the recipients died at a median of 20 days compared with 94% at a median of 15 days with CD28(+/+) cells (P < .001). Two million CD8(+) CD28(-/-) or CD28(+/+) T cells were transplanted into sublethally irradiated (750 cGy), MHC class-I incompatible (B6 x bm1) F1 recipients. With CD28(-/-) cells, 25% of the recipients died at a median of 41 days compared with 100% at a median of 15 days with CD28(+/+) cells (P < . 001). (B6 x bm12)F1 and (B6 x bm1)F1 mice surviving after transplantation of CD28(-/-) cells recovered thymocytes, T cells, and B cells in numbers and function comparable with that of irradiation-control F1 mice. We conclude that CD28 contributes to the pathogenesis and the severity of GVHD. Our results suggest that the severity of GVHD could be decreased by the administration of agents that block CD28 function in T lymphocytes.     

Soluble Fas levels in sera of bone marrow transplantation recipients are increased during acute graft-versus-host disease but not during infections

Graft-versus-host disease (GVHD) and infections are two major complications of allogeneic bone marrow transplantation (BMT). In the course of GVHD, one of the pathways that activated cytotoxic T cells use to execute their killing mechanisms is the Fas/Fas ligand pathway. This killing mechanism might be accompanied by the release of soluble Fas (sFas) in the circulation. To examine the association of serum sFas levels and post-BMT complications, we have analyzed sFas levels in sera of bone marrow recipients with and without GVHD. Postallogeneic BMT sFas levels were significantly increased during clinically relevant acute GVHD (aGVHD; P = .002). However, during infections sFas levels tended to decrease (P = .088). Yet, the simultaneous occurrence of GVHD and infections resulted in extreme high sFas levels. These results suggested that sFas release may be correlated with the amount of tissue damage, because aGVHD induces more damage than infections. The presence of significantly increased sFas levels during aGVHD provides new insights into the GVHD pathogenesis.     

Gastric graft-versus-host disease: a blinded histologic study

Acute graft-versus-host disease (GvHD) of the upper gastrointestinal (GI) tract is common after allogeneic bone marrow transplantation (BMT). However, diagnosis cannot be made on clinical presentation and endoscopic findings alone, because these are nonspecific, and histologic confirmation is often desirable. The diagnosis of gastric GvHD is often based on subtle findings with considerable potential for variability in interpretation. Evaluation of the reproducibility of diagnosis and recognition of histologic features of gastric GvHD was based on blinded review of 56 gastric biopsies (24 from patients with allogeneic BMT or unrelated umbilical cord blood transplantation and 32 control biopsies from patients who did not undergo BMT, of whom eight had active GI cytomegalovirus [CMV] infection). Histologic criteria for GvHD were apoptosis and gland destruction, sparse inflammatory infiltrate, and granular eosinophilic debris in dilated glands. Seventeen patients (22 biopsies) were judged to have clinical GvHD on the basis of skin or liver involvement and GI symptoms without other known cause. Eighteen of these 22 gastric biopsies were classified as GvHD by at least two of the three pathologists on initial review. Blinded histologic diagnosis of GvHD had a positive predictive value of 69%, a sensitivity of 82%, and specificity of 76%. False-positive results occurred in CMV gastritis, human immunodeficiency virus (HIV) infection, primary immunodeficiency, and after renal transplantation. Of individual features, granular debris in glands was a specific (94% specificity), but insensitive (41% sensitivity) marker for GvHD. Distinction between GvHD and CMV infection can be difficult, and GvHD can be confused with changes seen in HIV infection and other immunodeficiency states.     

Monoclonal antibodies in the treatment of steroid-resistant acute graft-versus-host disease

Acute graft-versus-host disease (GVHD) remains the major obstacle for successful allogeneic bone marrow transplantation (BMT). The frequency of grade II or higher acute GVHD ranges from 30-50% in human leukocyte antigen (HLA)-matched sibling transplants and 50-80% in HLA-matched unrelated transplants. The mortality and morbidity associated with this complication are substantial. Corticosteroid and polyclonal antibodies such as antithymocyte globulin (ATG) have had little success in treating the disease; however, advances have been made in hybridoma technology and understanding its immunopathophysiology. Based on these new insights, monoclonal antibodies, either murine or "humanized," were tested as rescue treatment for acute GVHD in human trials. Complete response rates ranged from 20-40%, with relapse occurring often. Side effects consisted of constitutional symptoms such as fever, chills, hypotension, thrombocytopenia, and leukopenia. Limitations of monoclonal antibody treatment included low response rate and patient survival, high relapse rate, risk of infectious complication, and leukemic relapse. Future study should focus not only on improved side effects and efficacy of monoclonal antibodies but also on better patient survival.     

"Suicide" gene for the control of graft-versus-host disease

OBJECTIVES: To determine the 10-year outcome of patients presenting with rest pain. METHODS: One hundred and three consecutive patients presenting with ischaemic rest pain in 1987 were followed up after 10 years. Hospital notes, death certificates and telephone interviews with patients were used to determine outcome. RESULTS: Follow-up data is available for 97 (94%) patients. Thirteen patients are alive (13.7%) after 10 years, 12 presented with rest pain alone and one had ulceration. Three of these had amputation. The commonest cause of death was myocardial infarction (n = 21, 25%). In those who had died, the median age of onset of symptoms was 72 years (49-93) for rest pain, 74 years (56-87) for ulceration and 71.5 years (45-85) for gangrene. Their survival after admission was a mean of 39 months with rest pain, 33 months with ulceration and 42 months with gangrene. The overall 5-year survival was 31% and the 10-year survival 13%. CONCLUSION: Patients presenting with ischaemic rest pain have a poor prognosis. The presence or absence of ulceration or gangrene does not influence the outcome. Most patients die from smoking-related diseases.     

Acute graft-versus-host disease in children: abdominal CT findings

PURPOSE: To review the computed tomographic (CT) appearance of acute gastrointestinal graft-versus-host disease (GVHD) in children. MATERIALS AND METHODS: Sixteen abdominal CT scans obtained in 12 children with acute gastrointestinal GVHD who underwent allogeneic bone marrow transplantation (BMT) were compared with 16 CT scans obtained in autologous bone marrow recipients not at risk for GVHD (control group). Autopsy findings in six patients with GVHD were compared with CT findings. RESULTS: All CT scans in patients with GVHD showed an abnormally enhanced, thin mucosal layer of bowel wall involving fluid-filled, dilated, poorly opacified bowel loops from the duodenum to the rectum. This corresponded histologically to mucosal destruction and replacement by a thin layer of highly vascular granulation tissue. Bowel wall thickening was often absent. Infiltration of mesenteric fat was seen in 91% of patients The control group showed no similar abnormalities. CONCLUSION: Acute gastrointestinal GVHD characteristically appears on CT scans as multiple, diffuse, fluid-filled bowel loops with a thin, enhancing layer of bowel wall mucosa. Bowel wall thickening often is absent.     

Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease

This study examines cerebrospinal fluid from patients with three neuropsychiatric diseases of childhood for the presence and levels of several cytokines relevant to cell-mediated (type 1) and humoral (type 2) immunity. The patient groups include childhood-onset schizophrenia (n = 22), obsessive-compulsive disorder (OCD) (n = 24), and attention deficit hyperactivity disorder (n = 42). The cytokines examined include IL-2, IFN-gamma, TNF-beta/LT, IL-4, IL-5, IL-10, and TNF-alpha. Patients with OCD had a preponderance of type 1 cytokines. IL-4 was detectable only in samples from patients with schizophrenia. IL-10 was rarely detected and never in patients with OCD. Few patients with schizophrenia had detectable amounts of IFN-gamma in CSFL. We conclude that there is a relative skewing of CSFL profiles toward type 1 cytokines in patients with OCD, whereas in schizophrenia the relative preponderance is toward type 2 mediators. Patients with attention deficit hyperactivity disorder exhibited profiles intermediate between OCD and schizophrenia. We infer that cell-mediated immunity may be involved in the etiopathogenesis of OCD, whereas a relative lack of cell-mediated immunity and involvement of humoral immunity may be present in schizophrenia. These data provide a rationale for immune-based strategies of study and therapeutics in childhood neuropsychiatric disease.