High-dose Immunosuppression Research Articles

Autologous Hematopoietic Stem Cell Transplantation for Type I Diabetes Mellitus.

Insulin-dependent type I diabetes mellitus (IDDM) is caused by autoimmune destruction of pancreatic β-islet cells mediated by inflammatory T cells. The pathogenic process evolves gradually for several years and becomes symptomatic when most Langerhans islands are destroyed. Antibodies against β-cell antigens (like anti-glutamic acid decarboxylase, GAD) are markers of the autoimmune reaction and levels of proinsulin C-peptide correlate with endogenous insulin secretion. Several immunosuppressive regimens have demonstrated clinical and laboratorial benefit in early onset IDDM, presumably sparing islets reserve, but most responses were transient and long term toxicity limited their continuous use. In view of durable remissions observed in various autoimmune diseases treated with high-dose immunosuppression and autologous hematopoietic stem cell transplantation (AHSCT), we started in December/03 a phase I/II trial of AHSCT in early-onset IDDM. Patients from 12–35 years old with <6 weeks from diagnosis have their peripheral blood stem cells mobilized with 2 g/m2 cyclophosphamide and 10 mcg/kg G-CSF, cryopreserved and reinfused (>2 million/kg) after conditioning with 200 mg/kg cyclophosphamide and 4,5 mg/kg rabbit antithymocyte globulin- ATG (Thymoglobuline, SangStat). End points of the study are insulin needs (U/kg/d), glycosilated hemoglobin levels, anti-GAD titers and C-peptide levels. Four patients have been transplanted and the insulin usage of the first three patients is shown in the Figure. The first patient received high dose of steroids to prevent ATG hypersensitivity and showed increasing needs of insulin after mobilization. The other two patients received minimal (#2) or no (#3) steroid dose during conditioning and showed decreasing needs of insulin after mobilization (Figure). Patient #2 presented bilateral pneumonia while pancytopenic, recovered after treatment with antibiotics and Amphotericin-B but did not require insulin therapy. A fourth patient has just been discharged from the BMT Unit. Immunologic studies in the three patients with longer follow-up showed a progressive shift from Th1 to Th2 cytokine profile after transplantation which could provide a mechanism for the modulation of the autoimmune process by high dose immunosuppression and autologous HSC. In conclusion, the preliminary results are encouraging but must be validated with a larger number of patients (12 planned in this phase) and a longer followup (5 years). [Display omitted]

FK778 attenuates lymphocyte-endothelium interaction after cardiac transplantation: in vivo and in vitro studies.

The malononitrilamide FK778 is a novel derivate of leflunomide and interacts with T- and B-cell function by inhibiting de novo pyrimidine synthesis. We investigated the effects of FK778 upon acute cardiac allograft rejection and upon adhesion molecule upregulation in experimental transplantation and by using in vitro cell culture. Heterotopic, abdominal cardiac transplantations were performed in the Brown Norway (BN) to Lewis (Lew) rat model. The study groups received daily low- or high-dose FK778 immunosuppression. FK778 plasma levels were quantified by HPLC. Grafts were harvested on the fifth postoperative day for histologic and immunohistologic examinations using computerized morphometry. Purified BN aortic endothelial cell cultures were pretreated with low- or high-dose FK778 according to FK778 plasma levels and were stimulated with tumor necrosis factor (TNF)-alpha. Adhesion molecule expression was quantified by immunofluorescence, FACS analysis, and Western blotting. Lymphocyte-endothelium adhesion assays were performed using purified Lew lymphocytes and radiolabeled TNF-alpha was used for receptor binding assays. FK778 treatment dose-dependently reduced graft mononuclear infiltration of CD4(+), CD8(+), and ED1(+) cells, but only high-dose FK778 treatment significantly reduced early upregulation of ICAM-1 and VCAM-1 in vivo. FK778 also dose-dependently reduced TNF-alpha-stimulated endothelial adhesion molecule upregulation in vitro, whereas the effect on VCAM-1 was more dominant. We did not find evidence that FK778 interferes with surface receptor binding of TNF-alpha. Lymphocyte adhesion to endothelial cell monolayers was significantly attenuated by FK778. Besides its inhibitory effect on pyrimidine synthesis, FK778 directly reduces endothelial adhesion molecule upregulation and attenuates lymphocyte-endothelium interaction, which is a critical step in graft rejection.

Multiple sclerosis

Autologous transplants for severe and refractory multiple sclerosis (MS) were proposed in 1997 and have been performed on about 200 selected patients worldwide. Phase I/II clinical studies have shown that high-dose immunosuppressive therapy suppresses inflammation in the CNS and may delay the progression of clinical disease. The procedure is associated with toxicity from the high-dose cytotoxic therapy and a risk of serious infections. There is a transplant-related mortality risk of 1–5%, requiring careful patient selection before transplantation. Treatment should be reserved for patients who have a significant chance of response, i.e. young patients with low disability scores but rapidly progressing disease who have inflammatory rather than neurodegenerative changes in the CNS. The long term effect of high-dose immunosuppression after transplantation on the frequency of relapse or progression of MS is unclear, but the initial concept of immune ablation by high-dose therapy and the reconstitution of normal immunity and tolerance from transplant-derived lymphocyte progenitors has given way to the concept of ‘resetting’ the immune system. The clinical effect of transplantation remains to be demonstrated in comparative studies.

Clinical Tolerance: the end of the beginning.

Clinical Tolerance: the end of the beginning.

High-dose immunosuppression and autologous hematopoietic stem cell rescue for severe multiple sclerosis.

Multiple sclerosis is a relatively common and seriously disabling disease of autoimmune pathogenesis, for which there is currently no cure. Available therapies include immunomodulating agents and standard-dose immunosuppressants, which may be helpful but are not curative. Recently, studies in animal models have indicated that control of autoimmune disease can be obtained by high-dose immunosuppression followed by hematopoietic stem cell transplantation (rescue). Autologous transplants for severe and refractory multiple sclerosis were proposed in 1997 and have been performed ever since in selected patients and in the context of phase I/II trials. To date, more than 200 patients have been treated worldwide, and similar results were obtained in different centers: high-dose therapy suppresses inflammation in the brain to a degree superior to any other conventional therapy and seems to delay significantly clinical disease progression. There is, however, a procedure-related mortality risk of 1.5-5%, requiring careful patient selection before transplant. The treatment should be reserved for patients having high chance of response, i.e., young patients with low disability scores but rapidly progressing disease, having inflammatory rather than neurodegenerative changes in the central nervous system. The mechanism of action of transplantation is unclear. The initial concept of immune ablation by high-dose therapy and reconstitution of normal immunity from transplant-derived lymphocyte progenitors has given way to the concept of "resetting" the immune system and of bringing the disease to a lower level of activity. One could also speculate on a tissue repair effect, given the ability of human hematopoietic stem cells to migrate also into the central nervous system. The clinical effect of transplantation remains to be demonstrated in a randomized study. The Autoimmune Disease Working Party of the European Group for Blood and Marrow Transplantation has launched such a trial, comparing transplantation to the currently best available therapy, i.e., mitoxantrone, and in about 5 years we should know whether transplantation offers more than the benefit of a transient immunosuppressive effect.

Initial experience with alemtuzumab in renal transplantation

T o be efficacious, immunosuppression regimens require long-term treatment, usually for the life of the patient. Unfortunately, the associated side effects, such as infection, cancer, renal damage, hypertension, diabetes, hyperlipidemia, hirsutism, cushingoid facial appearance, and bone necrosis, may be severe or life-threatening and have a direct impact on patient compliance, thus increasing the potential for rejection. In many cases, the resulting rejection is so far advanced that successful treatment for graft survival is unlikely. Consequently, a major goal of organ transplantation is to prevent rejection, induce graft tolerance, and minimize the use of longterm and high-dose immunosuppression. A pilot study was initiated in 1997 to study the efficacy of alemtuzumab (CAMPATH 1H; ILEXTM Oncology, Inc [ILEX], San Antonio, TX) as an induction therapy in 31 cadaveric renal transplant recipients. Patients received a single dose of alemtuzumab 20 mg intravenously on the day of and the day after transplantation followed by half doses of cyclosporine starting on the third postoperative day (Fig 1). Initial published results of the nonrandomized, open-label, single-center study indicated that alemtuzumab provided acceptable outcomes with high graft survival, low rejection rates, and low infection rates.1,2 Currently, the 5-year follow-up data show strikingly similar trends with a 71% graft survival rate, 84% patient survival rate, low infection rates with no late or unusual opportunistic infections observed, and no reports of malignancies (Figs 2 and 3). Importantly, patient compliance has been excellent

Post-transplantation lymphoproliferative disease in heart and heart–lung transplant recipients: 30-year experience at Stanford University

Background: Post-transplantation lymphoproliferative disease (PTLD) is an important source of morbidity and mortality in transplant recipients, with a reported incidence of 0.8% to 20%. Risk factors are thought to include immunosuppressive agents and viral infection. This study attempts to evaluate the impact of different immunosuppressive regimens, ganciclovir prophylaxis and other potential risk factors in the development of PTLD. Methods: We reviewed the records of 1,026 (874 heart, 152 heart–lung) patients who underwent transplantation at Stanford between 1968 and 1997. Of these, 57 heart and 8 heart–lung recipients developed PTLD. During this interval, 4 different immunosuppressive regimens were utilized sequentially. In January 1987, ganciclovir prophylaxis for cytomegalovirus serologic-positive patients was introduced. Other potential risk factors evaluated included age, gender, prior cardiac diagnoses, HLA match, rejection frequency and calcium-channel blockade. Results: No correlation of development of PTLD was found with different immunosuppression regimens consisting of azathioprine, prednisone, cyclosporine, OKT3 induction, tacrolimus and mycophenolate mofetil. A trend suggesting an influence of ganciclovir on the prevention of PTLD was not statistically significant ( p = 0.12). Recipient age and rejection frequency, as well as high-dose cyclosporine immunosuppression, were significantly ( p < 0.02) associated with PTLD development. The prevalence of PTLD at 13.3 years was 15%. Conclusions: The overall incidence of PTLD was 6.3%. It was not altered by sequential modifications in treatment regimens. Younger recipient age and higher rejection frequency were associated with increased PTLD occurrence. The 15% prevalence of PTLD in 58 long-term survivors was unexpectedly high.

Improvement in human decay accelerating factor transgenic porcine kidney xenograft rejection with intravenous administration of gas914, a polymeric form of alphaGAL.

The present study was undertaken to determine whether intravenous administration of GAS914, a polymeric form of alphaGal, would minimize porcine kidney xenograft rejection in baboons. Human decay accelerating factor renal xenografts were transplanted into 16 baboon recipients. Baseline immunosuppression for all groups included cyclosporine A, cyclophosphamide, SDZ-RAD, and methylprednisolone. Group 1 received only baseline immunosuppression; group 2 animals received low-dose GAS914 with baseline immunosuppression; group 3 animals received high dose GAS914 with high-dose baseline immunosuppression; and animals from group 4 received high-dose GAS914 and low-dose baseline immunosuppression. None of the animals in this study developed hyperacute rejection. Intravenous administration of GAS914 significantly reduced xenoreactive antibodies as measured by antiporcine hemolytic assays and anti-Gal (immunoglobulin [Ig] G and IgM) antibody assays. Rejection was less severe in the GAS914-treated group. Only 25% (3 of 12) of GAS914-treated animals were killed as a result of rejection, whereas 75% (three of four) of non-GAS914-treated animals were killed because of terminal rejection (P<0.01). Protocol biopsies demonstrated that the degree of acute humoral xenograft rejection (AHXR) was reduced in the GAS914-treated animals compared with non-GAS914-treated animals. The intravenous administration of GAS914 reduces xenoreactive antibody levels and reduces the degree of porcine kidney xenograft rejection, but does not improve survival. AHXR and drug toxicity remain major barriers to the long-term success of xenotransplantation.

Narrowband UV-B phototherapy in the treatment of cutaneous graft versus host disease.

Graft versus host disease (GVHD) is an important problem following allogenic bone marrow transplantation (BMT). The beneficial effects of photochemotherapy with psoralens plus UVA irradiation (PUVA) have been described repeatedly; however, PUVA is limited by a wide range of unwanted effects. A novel improved form of UV-B phototherapy, narrowband UV-B, has been proven to be very effective in T-cell mediated dermatoses. Therefore, we investigated the effect of narrowband UV-B phototherapy (5 times per week) in 10 patients with cutaneous GVHD (grade 2-3) resistant to standard immunosuppressive drugs. It was tolerated well by all patients, and no side effects were observed. Skin lesions showed complete clearance in 7 out of 10 patients within 3 to 5 weeks. 3 patients showed significant improvement of GVHD. We suggest that narrowband UV-B phototherapy is a nonaggressive treatment that may benefit patients with cutaneous GVHD who already take high doses of immunosuppressive drugs.

High-Dose Immunosuppression for Refractory CIDP?

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated neuropathy for which treatment with plasma exchange, intravenous

Non-endocrine late complications of bone marrow transplantation in childhood: part II.

Non-endocrine late complications of bone marrow transplantation in childhood: part II.

Down-regulated donor-specific T-cell reactivity during successful tapering of immunosuppression after kidney transplantation.

Stable cadaveric renal transplant patients were routinely converted from cyclosporin A (CsA) to either azathioprine (AZA) or mycophenolate mofetil (MMF) 1 year after transplantation to reduce the side effects of long-term immunosuppressive therapy. Thereafter, the AZA and MMF dose was gradually tapered to 50% at 2 years after transplantation. We questioned whether a reduction of immunosuppressive treatment results in a rise of donor-specific T-cell reactivity. Before transplantation (no immunosuppression), 1 year (high dose immunosuppression) and 2 years (low dose immunosuppression) after transplantation, the T-cell reactivity of peripheral blood mononuclear cells (PBMC) against donor and third-party spleen cells was tested in mixed lymphocyte cultures (MLC) and against tetanus toxoid (TET) to test the general immune response. We also measured the frequency of donor and third-party reactive helper (HTLpf) and cytotoxic (CTLpf) T-lymphocyte precursors in a limiting dilution assay. Donor-specific responses, calculated by relative responses (RR = donor/third-party reactivity), were determined. Comparing responses after transplantation during high dose immunosuppression with responses before transplantation (no immmunosuppression), the donor-specific MLC-RR (P = 0.04), HTLp-RR (P = 0.04) and CTLp-RR (P = 0.09) decreased, while the TET-reactivity did not change. Comparing the responses during low dose with high dose immunosuppression, no donor- specific differences were found in the MLC-RR, HTLp-RR and CTLp-RR, although TET-reactivity increased considerably (P = 0.0005). We observed a reduction in donor-specific T-cell reactivity in stable patients after renal transplantation during in vivo high dose immunosuppression. Tapering of the immunosuppressive load had no rebound effect on the donor-specific reactivity, while it allowed recovery of the response to nominal antigens.

Importance of physical rehabilitation before and after cardiac transplantation in a patient with myotonic dystrophy: A case report

Conraads VM, Beckers PJ, Vorlat A, Vrints CJ. Importance of physical rehabilitation before and after cardiac transplantation in a patient with myotonic dystrophy: a case report. Arch Phys Med Rehabil 2002:83:724-6. Patients with muscular dystrophy and concomitant cardiomyopathy are only reluctantly accepted for heart transplantation because of the perioperative risk secondary to respiratory muscle weakness. We describe a man with Steinert's disease (myotonic dystrophy) who received a cardiac allograft because of end-stage dilated cardiomyopathy. This case shows the importance of uninterrupted physiotherapeutic training and assistance to minimize respiratory infections and ventilatory insufficiency in patients with muscle diseases under high-dose immunosuppression. To our knowledge, this is the first heart transplantation reported in a patient with Steinert's disease who has clinically overt muscular impairment. © 2002 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

High-dose immunosuppression and hematopoietic stem cell transplantation in autoimmune disease: clinical review.

Since 1996, a number of investigators have carried out phase I-II studies of high-dose immunosuppression with autologous hematopoietic stem cell transplantation (HSCT) in autoimmune diseases. Most of this activity has been in studies of multiple sclerosis (MS), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and juvenile idiopathic arthritis (JIA). Supported by animal models of antigen-induced autoimmunity, the rationale of HSCT is to time-shift the clinical autoimmunity to an earlier period, restoring self-tolerance. Even with the considerable experience of more than 200 transplantations since 1996, it is difficult to judge the optimal approach. This difficulty is in part because of the multiplicity of centers and protocols and the variability in patient eligibility and assessment, the extent of T-cell depletion, and the intensity of the preparatory regimens used. Other than that found in RA, treatment-related mortality has been higher than expected: 17% in SSc (with an additional 10% mortality from progressive disease), 13% in SLE, 13% in JIA, and 8% in MS. Protocol changes to improve safety have been instituted. These changes include the avoidance of high-dose rabbit antithymocyte serum in patients who received T-cell-depleted grafts, use of corticosteroids with granulocyte colony-stimulating factor during stem cell mobilization and as prophylaxis for the engraftment syndrome in MS, lung radiation shielding in SSc, and multiple precautions against the macrophage activation syndrome in JIA. Responses to primary and secondary endpoints have been seen, and there is a consensus among investigators and regulatory bodies that the time has come for randomized phase II-III studies. Each disease presents distinct difficulties: in MS, restriction of eligibility to patients with active inflammatory disease; in SSc, formulation of cardiopulmonary eligibility criteria to decrease risk; in SLE, judgment of whether HSCT adds any advantage to high-dose nonmyeloablative immunosuppressive treatment alone; and in RA, enhancement of response durability. All prospective randomized studies in these diseases must address problems in selection of the comparison nontransplantation treatment and appropriate stopping rules, particularly with treatment arms of unequal risk. Parallel trials in Europe and in the United States are in the late stages of design.

Squamous cell carcinoma of the head and neck in solid organ transplant recipients.

The increased incidence of cancer after solid organ transplantation is well established in the literature, yet outcome studies in this population are rare. Excluding skin cancers, squamous cell carcinomas make up most head and neck cancers in transplant recipients. At our institution, of 5300 solid organ transplant recipients, 34 have had head and neck cancer develop. We reviewed the records of the 23 recipients whose cancer was treated here. Only 6 of the 23 recipients were alive at the time of our chart review. Of these, three had already survived 5 years. The 10 recipients diagnosed early (stage I or II) had significantly longer survival after cancer diagnosis than the 13 diagnosed at an advanced stage (stage III or IV) (96.0 mo vs 9.0 mo, p <.001). In all, 14 (60.8%) of the 23 recipients died of cancer within 2 years after diagnosis, 12 (50.2%) within 12 months. The sum of the daily doses of immunosuppressive drugs at cancer diagnosis was significantly greater for recipients who died within 2 years (p =.02). Furthermore, the difference in average doses of both prednisone (p =.001) and azathioprine (p =.028) was also significantly greater for those who died within 2 years. The average dose of cyclosporine was also greater, but this difference did not reach statistical significance (p =.18). The average dose of prednisone was significantly lower for recipients diagnosed early (p =.001). This correlation between high immunosuppressive drug doses and worse outcome has not been shown previously. Solid organ transplant recipients who are diagnosed with advanced head and neck cancer while receiving high doses of immunosuppressive drugs fare extremely poorly. High doses of immunosuppressive drugs, most notably prednisone, correlate significantly with advanced diagnosis of head and neck cancer and earlier death.

Successful Bone Marrow Plus Cord Blood Stem Cell Transplantation in a Girl who Developed Myelodysplastic Syndrome from Hepatitis-associated Aplastic Anemia Treated with Long-term Immunosuppressants and Growth Factors

A 9-year-old girl who had hepatitis-associated aplastic anemia was treated intermittently with methylprednisolone pulse therapy and growth factors (granulocyte-colony stimulating factor (G-CSF), recombinant human erythropoietin (rhEpo) and cyclosporin A (CyA) for over two years. At this time, there was hematological improvement, but chromosome analysis revealed monosomy 7.After six months, there was progression to myelodysplastic syndrome (MDS) (stage in refractory anemia of excess blasts (RAEB)) with monosomy 7, monosomy 6, marker chromosome and with hematological deterioration.She received bone marrow (1.57×105 cells kg−1 (patient body weight)) plus cord blood cell (0.3×107 cells kg−1 (patient body weight)) transplantation from her brother, 2 years and 7 months after the diagnosis of hepatitis-associated aplastic anemia. Engraftment was achieved after two weeks, and acute graft-versus-host disease occurred in a mild form after four weeks. Hematological remission has been continuous for 20 months after bone marrow transplantation. Transformation of hepatitis-associated aplastic anemia to MDS with the monosomy 7, monosomy 6 and marker chromosome in this patient was considered to have been related to the administration of high doses of immunosuppressive drugs plus growth factors.

Autologous stem cell transplants in treatment of multiple sclerosis: where we stand and future prospects.

Based on experimental and clinical observations, high-dose immunosuppression followed by autologous transplantation may induce remissions in severe, refractory, autoimmune disorders including multiple sclerosis, a disease which, in its progressive form, does not respond to treatment. Phase I/II studies of transplantation in MS published by individual centers as well as a comprehensive analysis of the reports to the EBMT registry have shown that transplantation may positively affect MS by stabilizing the clinical condition of the patients, by improving their disability status, and by completely abrogating the inflammatory process in the brain as evidenced in magnetic resonance imaging. Other available therapies do not appear to be so efficacious as transplantation. However, the procedure is associated with a transplant-related mortality risk of about 3 to 8%. Therefore, it cannot be recommended for the treatment of a chronic, non-lethal, disease like MS unless it proves superior to standard therapies in terms of efficacy. This can be demonstrated only in a randomized trial, which is being launched by the EBMT under the name ASTIMS. It compares the BEAM regimen plus autotransplantation to mitoxantrone, which is currently regarded as one of the best available treatments, in patients with secondary progressive or rapidly evolving relapsing/remitting multiple sclerosis.

ICOS costimulation in inflammatory bowel disease.

For years, medical researchers have striven to develop selective immunotherapies that could specifically ameliorate pathogenic immune responses without immunocompromising the patient. Blockade of many known receptors on T cells can inhibit the initiation of immune responses. However, this approach is problematic in that it is not possible to predict the onset of disease in patients. Current immunotherapies are unsatisfactory for the sporadic exacerbating type of diseases such as multiple sclerosis and inflammatory bowel disease (IBD), because they require either long-term treatment or acute treatment with high-dose immunosuppressants. With regard to this issue, the inducible and inflammatory site-specific molecule, inducible costimulator (ICOS), may be particularly useful as an ideal targeting molecule for the strategy of treatment of human IBD patients.

Bone Marrow Stem Cells and Stromal Cells in Autoimmune Cytopenias

High-dose immunosuppression followed by autologous haemopoietic stem cell transplantation (ASCT) is a promising practice for the treatment of severe, resistant autoimmune disorders. Patients with refractory autoimmune cytopenias (AIC), primary or secondary to systemic autoimmune diseases (AID) including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), have been proposed as potential candidates for such a therapeutic procedure. An abnormal immune milieu, however, may affect the number and functional characteristics of stem cells and/or stromal cells in the bone marrow (BM) and might impact on harvesting and engraftment potential of stem cells or on BM reconstitution following engraftment in patients with AIC undergoing ASCT. Using flow cytometry and in vitro culture assays we have shown that patients with primary AIC display increased number of BM CD34 + cells in response to abnormally high production of granulocyte-colony stimulating factor (G-CSF) by BM stroma. In contrast, patients with AIC secondary to systemic AID display increased apoptosis of BM progenitor cells resulting in low CD34 + cell numbers and abnormal haemopoiesis supporting capacity of BM stroma due to the aberrant, local or systemic, inhibitory cytokine production or to intricate interactions between haemopoietic and immune cells present within the BM microenvironment. In this review we summarize the available knowledge on BM stem cell reserve and function and stromal cell function in patients with primary and secondary AIC with special reference to SLE and RA. The underlying mechanisms possibly involved in the pathogenesis of the observed abnormalities are also discussed.

Factor XIII replacement in stem cell transplant (SCT) recipients with severe graft-versus-host disease of the bowel: report of an initial experience.

Severe acute graft-versus-host disease (aGVHD) of the gut is a serious and frequent posttransplantation event associated with a high mortality rate. We report on our experience with factor XIII replacement in patients with severe aGVHD of the bowel after allogeneic hematopoietic stem cell transplantation. Twenty-seven patients after allogeneic stem cell transplantation and severe aGVHD of the gut were enrolled. All patients suffered from bloody diarrhea that required packed red blood cell infusions. All patients received high-dose immunosuppression in combination with coagulation factor XIII (5,000 units initially, followed by 20 IU/kg body weight three times a day) for up to 3 weeks. After 8 days of factor XIII replacement and unchanged high-dose immunosuppression, we observed a significant reduction in the red blood cell requirement of 21 patients. We conclude that factor XIII replacement might be a useful supplementation in the treatment of aGVHD of the bowel.