Cyclosporin A versus methotrexate, followed by rescue with folinic acid as prophylaxis of acute graft-versus-host disease after bone marrow transplantation

Fifty-seven patients undergoing bone marrow transplantation were randomly assigned to receive either cyclosporin A (CsA, n = 26) or methotrexate, followed by rescue with folinic acid (MTX + FA, n = 31) as prophylaxis for graft-versus-host disease (GVHD). All patients but one receiving CsA had evidence of sustained engraftment, and there was no difference between the two groups on the day in which marrow engraftment was documented. Oropharyngeal mucositis was of similar incidence and severity in the two groups. In contrast, patients receiving CsA showed higher renal and hepatic toxicity rates than those treated with MTX + FA. Severe-to-moderate acute GVHD (grades II-IV) was documented in 12 patients receiving CsA and in 12 treated with MTX + FA. The cumulative incidence of this complication was similar in both groups (46.1% and 38.7%). Similarly, there was no difference in the incidence of chronic GVHD. The leukemic relapse rates were also comparable, as well as the estimated probability of survival, which was 55% in patients treated with MTX + FA and 41% in those who were given CsA. We conclude that MTX + FA is as effective as CsA in the prevention of GVHD, with the additional advantage of reduced renal and hepatic toxicities.     

Transfusion-associated graft-versus-host disease.

The clinical pathologic syndrome of graft-versus-host disease (GVHD) is usually a sequela of bone marrow transplantation. This disorder occurs as a result of recognition by engrafted donor-derived lymphocytes of "foreign" recipient transplantation antigens. GVHD may also result from engraftment of lymphocytes from other sources, including (1) transfusion of lymphocytes containing blood components, (2) transplacental maternal fetal transfusion, and (3) passive transfer of lymphocytes in solid organ transplantation. The recipients are usually severely immunodeficient and thus incapable of rejecting the transfused lymphocytes. This syndrome may, however, also develop in immunologically competent patients receiving blood products from individuals with histocompatibility antigens not recognized as foreign.     

Skin rejection in graft-versus-host disease.

Graft-versus-host disease is becoming a common clinical problem, one which can require the consultation of a plastic surgeon for restoration of skin coverage. An understanding of the immunological basis of the disease is essential to the clinical management of this condition. A case of GVHD is reported, and the principles of treatment are discussed.     

Cyclosporin A in cadaveric organ transplantation.

The use of cyclosporin A (CyA) with a protocol designed to avoid the effects of nephrotoxicity resulted in a one-year survival of 86% in recipients of renal allografts from unmatched cadaveric donors. The drug also controlled rejection of liver and pancreatic allografts. It was possible to change patients initially treated with CyA to azathioprine and corticosteroids and vice versa, thus enlarging the potential value of CyA in organ allografting. Of 34 recipients of renal allografts, 29 were currently receiving only CyA as immunosuppressive treatment. Twelve patients never required any adjuvant steroid treatment. These results suggest that CyA is an effective immunosuppressant, and if used with care side effects need not be severe.     

Immunodeficiency in graft-versus-host disease. I. Mechanism of immune suppression

Irradiated CBA/J mice transplanted with H-2 compatible, minor histocompatibility disparate B10.BR bone marrow develop graft-versus-host disease (GVHD) if mature T lymphocytes are added to the marrow inoculum. In the setting of mild GVHD (receiving 10(4) or 10(5) T cells), by phenotypic analysis, lymphoid reconstitution occurs normally within 4 to 6 wk but there is a profound deficiency in the ability of splenic lymphocytes to respond to polyclonal activators such as LPS and Con A. This unresponsiveness is attributable to active suppression mediated by cells that express Thy-1 and can be removed with leucine methyl ester treatment. Thus, splenocytes from mice with GVHD suppress responses of normal T and B lymphocytes. Moreover, depletion of these suppressor cells restores normal function to splenocytes from mice with GVHD, and B cells isolated from these mice respond normally to T-dependent and -independent stimulation. Finally, IFN-gamma plays an important role in this suppression, because a neutralizing anti-IFN-gamma mAb significantly removes suppression of normal cells and restores functional responses of lymphocytes from mice with GVHD. These results provide insights into the mechanisms of immunodeficiency associated with GVHD, and suggest novel strategies for possible therapies for this disorder.     

Cyclosporin A-induced autologous graft-versus-host disease: a prototypical model of autoimmunity and active (dominant) tolerance coordinately induced by recent thymic emigrants.

Cyclosporin A (CSA)-induced autologous graft-vs-host disease (autoGVHD) is an autoimmune syndrome initiated by autoeffector T cells presumed to be exported from the thymus during CSA treatment. The appearance of noncytotoxic immunoregulatory T cell activity after cessation of CSA treatment is also thymus dependent. In the present study, we have tested the hypothesis that both autoeffector and immunoregulatory T cells in CSA-treated rats are recent thymic emigrants (RTEs). Local syngeneic graft-vs-host reaction (synGVHR) and timed thymectomy (Tx) assays revealed that autoeffector T cells appear initially in the thymus and are promptly exported to lymph nodes (LN) during the first week of CSA treatment. In contrast, immunoregulatory thymocytes are first detectable by local synGVHR inhibition assays during the second week of CSA treatment but are not exported to LN until approximately 4 days post-CSA. Both the autoeffector and immunoregulatory T cells in LN express Thy-1, a selective marker for RTEs in the rat. However, the autoeffector RTEs have a CD4+8+ phenotype, whereas the immunoregulatory RTEs have a CD4+8- phenotype. Thus, the coordinate formation in and release from the thymus cortex and medulla of autoeffector and immunoregulatory T cells in CSA-treated rats directly demonstrates that centrally induced, nondeletional tolerance can serve as a fail-safe mechanism by which clones of autoeffector T cells that have escaped intrathymic negative selection for self-MHC class II Ag can be suppressed postthymically.     

Low-dose heparin prophylaxis against fatal pulmonary embolism.

A prospective randomised controlled trial in 500 patients over the age of 50 who were undergoing major surgery showed that low-dose subcutaneous heparin was an effective prophylactic measure against fatal pulmonary embolism. None of the 252 patients who received perioperative heparin cover died of fatal pulmonary embolism while eight of the 236 who did not receive heparin prophylaxis died of fatal pulmonary embolism. These results were statiscally significant (P less than 0.01).     

Tolerance, mixed chimerism and protection against graft-versus-host disease after total lymphoid irradiation

Total lymphoid irradiation (TLI), originally developed as a non-myeloablative treatment for Hodgkin's disease, has been adapted for the induction of immune tolerance to organ allografts in rodents, dogs and non-human primates. Moreover, pretransplantation TLI has been used in prospective studies to demonstrate the feasibility of the induction of tolerance to cadaveric kidney allografts in humans. Two types of tolerance, chimeric and non-chimeric, develop after TLI treatment of hosts depending on whether donor bone marrow cells are transplanted along with the organ allograft. An advantageous feature of TLI for combined marrow and organ transplantation is the protection against graft-versus-host disease (GVHD) and facilitation of chimerism afforded by the predominance of CD4+ NK1.1(+) -like T cells in the irradiated host lymphoid tissues. Recently, a completely post-transplantation TLI regimen has been developed resulting in stable mixed chimerism and tolerance that is enhanced by a brief course of cyclosporine. The post-transplantation protocol is suitable for clinical cadaveric kidney transplantation. This review summarizes the evolution of TLI protocols for eventual application to human clinical transplantation and discusses the mechanisms involved in the induction of mixed chimerism and protection from GVHD.     

Novel role for surfactant protein A in gastrointestinal graft-versus-host disease

Graft-versus-host disease (GVHD) is a severe and frequent complication of allogeneic bone marrow transplantation (BMT) that involves the gastrointestinal (GI) tract and lungs. The pathobiology of GVHD is complex and involves immune cell recognition of host Ags as foreign. We hypothesize a central role for the collectin surfactant protein A (SP-A) in regulating the development of GVHD after allogeneic BMT. C57BL/6 (H2b; WT) and SP-A-deficient mice on a C57BL/6 background (H2b; SP-A(-/-)) mice underwent allogeneic or syngeneic BMT with cells from either C3HeB/FeJ (H2k; SP-A-deficient recipient mice that have undergone an allogeneic BMT [SP-A(-/-)alloBMT] or SP-A-sufficient recipient mice that have undergone an allogeneic BMT) or C57BL/6 (H2b; SP-A-deficient recipient mice that have undergone a syngeneic BMT or SP-A-sufficient recipient mice that have undergone a syngeneic BMT) mice. Five weeks post-BMT, mice were necropsied, and lung and GI tissue were analyzed. SP-A(-/-) alloBMT or SP-A-sufficient recipient mice that have undergone an allogeneic BMT had no significant differences in lung pathology; however, SP-A(-/-)alloBMT mice developed marked features of GI GVHD, including decreased body weight, increased tissue inflammation, and lymphocytic infiltration. SP-A(-/-)alloBMT mice also had increased colon expression of IL-1β, IL-6, TNF-α, and IFN-γ and as well as increased Th17 cells and diminished regulatory T cells. Our results demonstrate the first evidence, to our knowledge, of a critical role for SP-A in modulating GI GVHD. In these studies, we demonstrate that mice deficient in SP-A that have undergone an allogeneic BMT have a greater incidence of GI GVHD that is associated with increased Th17 cells and decreased regulatory T cells. The results of these studies demonstrate that SP-A protects against the development of GI GVHD and establishes a role for SP-A in regulating the immune response in the GI tract.     

Cyclosporin A: a powerful immunosuppressant.

Cyclosporin A (CyA) is a powerful immunosuppressive agent whose lack of myelotoxicity makes it unique among nonsteroidal drugs currently given for immunosuppression. It has been used with initial success in recipients of kidney, liver, bone marrow and pancreas transplants, and it may also have clinical application in the treatment of autoimmune disorders. In regard to its use in transplant recipients, there are many remaining questions about its mechanism of action, the optimum dose, whether it should be used alone or with other immunosuppressants, whether it can suppress chronic rejection and what its long-term side effects may be. These questions can only be answered by further careful laboratory investigation and controlled clinical trials. Until then, CyA should only be administered in centres experienced in its use.     

Acute graft-versus-host disease after allogeneic bone marrow transplantation.

In 25 patients receiving allogeneic bone marrow transplants methotrexate was used to prevent acute graft-versus-host disease (GVHD). Acute GVHD, grades 2 to 4, developed in only 5 (20%) of the patients. The incidence of acute GVHD in other series of recipients of bone marrow transplants has ranged from 5% to 76%. A review of the literature suggests that this variation cannot be completely accounted for by age, type of disease treated by transplantation or type of GVHD prophylaxis. However, transfusion of allogeneic lymphocytes that have not been completely inactivated by irradiation (e.g., in platelet and granulocyte preparations) and inadequate isolation-decontamination procedures may increase the probability of GVHD following bone marrow transplantation.