Bone Marrow Transplantation and the Graft-Versus-Host Disease - Assignment Example

Section I- Research Background This section provides the history of the researches associated with GVHD in BMT and its common causes. It also discusses the prevalent prevention strategies as suggested by some of the recent researches. Introduction Bone marrow transplant surgery commonly considered a highly successful medical therapy for treatment of cancer. The BMT has not only been touted as one of the most effective procedures for controlling spread of cancer in the patient’s body, but is also considered as one of the less time consuming therapies for cancer control. However, the success rate of BMT has been marred by sever side effects that have been recently discovered through various new researches. The high risk involved in a BMT evolves from the fact that the new transplanted cells can also attack the patient body thereby damaging the cell structure and internal organs. This side effect has been termed as the Graft-Versus-Host Disease (GVHD), and has been found to be recurring in a high percentage of cancer patients annually. The active immune cells in the transplanted marrow often cause GVHD. These cells tend to attack the host body, considering it as a foreign entity. The image below presents the impact of GVHD: (Source: http://igrid-ext.cryst.bbk.ac.uk/WWW/PhD_thesis_files/image032.jpg Though various drugs and steroids are used for preventing GVHD, yet their impact is not long lasting and is accompanied by sever side effects such as violent mood swings and bone deterioration which can even prove to be fatal in some cases. (http://www.articlebase.info/Article/All-Bones-About-It--New-Treatment-For-GVHD/4614) The failure of steroids to provide a reliable treatment for GVHD has prompted many researches to discover newer therapies for countering GVHD. In this regard, the most popular researches have been conducted for gauging the impact of dendritic cell surface activation antigen of CD83. The dendritic cell surface activation antigen of CD83 has been found to be an antibody for GVHD. Various researched have been conducted to gauge the impact of Antibody to the dendritic cell surface activation antigen CD83 on graft-vs.-host disease (GVHD). A murine allogeneic bone marrow transplantation model studied by B. Turner et al. indicated that the antigen-presenting cells which were derived from the host initiated GVHD. This happens despite the presence of numerous donor antigen-presenting cells in the host body. Therefore, the research team concluded that medical methods for preventing GVHD could be developed by examining the inactivating host antigen-presenting cells. If these therapies do find clinical success, they can prove to be highly significant in preventing GVHD. In addition, the success of these therapies would also increase the success allogeneic bone marrow transplantation which is a required procedure during the treatment of common genetic and neoplastic diseases. (B.Turner et al, 2008). On similar lines, the research done by David J. Munster, et al. shows that a CD83 antibody treatment prevented GVHD. However, their research also indicated that unlike conventional immunosuppressant, CD83 failed to prevent engraftment of human T cells that include cytotoxic T lymphocytes which is highly vulnerable to viruses and other malignant cells. GVHD and the associated risks GVHD is a common complication that may occur after a BMT or any stem cell transplant. The primary cause of GVHD is that the transplanted cells consider the patient body as a foreign body and begin to attack the host tissues. GVHD is a severe life threatening infection that also has a high mortality rate; therefore, in the last decade numerous researchers have conducted various studies and trials to decipher new ways of treating it or at least reducing its symptoms. (Reducing the risk of graft-versus-host disease after bone marrow transplant, 2006) Further, multivariate analysis in a study conducted by Rima M Saliba et al. established the following as primary factors behind GVHD: A mismatched related or matched unrelated donor A myeloablative conditioning regimen, More than 5 prior chemotherapy regimens Donor-recipient sex mismatch Broadly, GVHD can be classified as acute GVHD and chronic GVHD. In the case of acute GVHD, the common symptoms include reddish skin rash, as well as nausea and diarrhoea. These symptoms usually appear within three months of a transplant. In case the recipient’s liver has been impacted by GVHD the skin may begin to turn yellow. In case of chronic GVHD also the symptoms show after three months of the transplant. Usually the symptoms of chronic GVHD are usually rated as mild to severe. Though the symptoms of chronic GVHD resemble that of GVHD, yet they can also include infection in the salivary glands in the mouth and the mucous glands of the eyes. Chronic GVHD can last from several months to many years. (http://www.wdxcyber.com/gvhd.html) During various researches conducted over GVHD, one fact remains common- that is- T cells in the recipient’s body are the primary trigger for GVHD following a BMT. The differences in the antigens presented to T cells by GVHD target tissues and by recipient malignant cells that form the basis for approaches to separate GVHD from useful donor immunity. The same is also substantiated by David J. Munster et al. In the paper, Antibody to the dendritic cell surface activation antigen CD83 prevents acute graft-versus-host disease, the researchers mention that reception of radiation and chemotherapy at the recipient’s end enables the donor haematopoietic and immune systems to implant and provide immune effectors. These immune effectors confer protective immunity to the recipient and also provide the desired therapeutic graft versus leukaemia (GVL) effect for leukaemia patients. The paper further cites that in the related study conducted it was found that the donor T cell mediated acute graft-versus-host disease (GVHD). This T cell targets recipient skin, gut, liver, lung, and lymphoid tissue, is an inevitable consequence of allogenic HSCT. It is also a major cause of morbidity and mortality amongst patients who undergo BMT. The challenge for the researchers is to device a therapy for selecting or removing T cells in such a manner that the risk of GVHD is greatly reduced. An interesting aspect about T cells and GVHD has been put forth by Wysocki et al. This team suggests that GVHD is triggered by T cells from the donor which have the ability to recognize differences in histocompatibility of either the recipient or the host. This then, leads to T cell activation, proliferation and finally causes tissue destruction in the host. Since the T cells are given into the intravenous system, they spread to specific tissues such as the liver, GI tract or skin and cause the damage associated with GVHD. The findings suggest that this resultant engraftment takes place in a lymphoid tissue such as lymph nodes and the spleen. Also, the resulting development of tissue GVHD occurs in sync with the activity of trafficking receptors on the T cells following the interaction with host cells in lymphoid sites. Therefore, conclusively that blocking T cell migration using FTY 720 may prevent GVHD, but may not be able to treat it in already infected patients. The figure below demonstrates the framework established by Wysocki et al. Guimond et al have also provided an elaborate framework for selectively removing all activated T cells from the T-cell collection. This framework can be the basis of a clinical application for the removal of T cells that trigger GVHD after a transplant. A similar framework has also been cited by David J Munster et al. in their paper Antibody to the dendritic cell surface activation antigen CD83 prevents acute graft-versus-host disease, wherein, the researchers suggest that inducing certain components into T cells, which do not alter any T cell properties, but prevent them from triggering GVHD can be a plausible therapy for controlling the risk of GVHD following a BMT. A similar technique for preventing GVHD has also been suggested by Warren D Sholmchik et al. This team of researchers suggest that GVHD is essentially an aftermath of the alloimmune attack on host tissues mounted by donor T cells. The therapies for preventing GVHD can be based on the idea of inactivating host antigen-presenting cells, because typically in the case of a murine allogeneic bone marrow transplantation the presence of numerous donor antigen-presenting cells had no impact on GVHD while only the host-derived antigen-presenting cells initiated GVHD. (Warren D. Shlomchik, et al., 1999) GVHD is also the most common complication associated with stem cell transplant (SCT). In case of SCT as well allogeneic SCT is recommended for older patients who are more vulnerable to developing GVHD. In addition, there is an emphasis on using unrelated donors and related but nonhuman leukocyte antigen (HLA)-identical donors to control GVND. A recent suggestion in this regard states that patients receiving allogeneic peripheral blood stem cell transplants have a lower risk acute GVHD but an equally high risk of chronic GVHD as compared to the patients receiving marrow grafts. Therefore, chronic GVHD is looked upon as a prominent hindrance in the field of blood and marrow transplantation. (Bone Marrow Transplantation (2008) 41, 887–893; doi:10.1038/sj.bmt.1705987; published online 21 January 2008) Finally a glance at the mortality rates amongst patients infected with GVHD: Section II-Literature Analysis of the paper, Antibody to the dendritic cell surface activation antigen CD83 prevents acute graft-versus-host disease In this section, we will discuss the hypothesis and theoretical framework used by David J Munster et al. in the light if the research background presented above and compares it with similar/contradictory researches in this field. Synopsis of the paper: David J Munster et al. conducted various studies of mice, rabbit and human T cells. The research paper based on these studies cites that treatment of allogenic mixed lymphocyte cultures with activated human DC-depleting CD83 antibody suppressed alloproliferation while preserving the T cell numbers, including those specific for CMV. The team also tested a CD83 antibody in the human T cell. Finally, it was shown that the mouse model used required a human DC and that CD83 antibody treatment prevented GVHD. Paper Background The team of researchers argues that though allogeneic haematopoietic stem cell transplantation is an effective therapy for haematological malignancies, yet its effectiveness is reduced by GVHD. Also, dendritic cells (DC) play a major role in the allogenic T cell stimulation causing GVHD. The prevalent immunosuppressive measures to control GVHD though target T cells, yet this treatment reduces the post transplant immunity in the patient, especially to cytomegalovirus (CMV) and residual malignant cells. The team, through its studies, showed that immunization of CD83 antibody induced allogenic antileukemic CTL effectors in vivo that mixed leukemic target cells in vitro without further stimulation. In addition, activated DC is a promising new therapeutic approach to the control of GVHD. In this regard, the mouse allogenic HSCT models indicate that the donor anti host T cell response is stimulated by direct alloantigen presentation by the host APC, particularly DC. In addition, donor APC contribute, presumably via the indirect pathway by processing and presenting host antigens to donor T cells. Several recent researches have shown that donor APC may be an appropriate therapeutic target as APC propagate GVHD initiated by host APC and that they can independently induce GVHD while playing a significant role in HSCT rejection. Though prophylactic, and often additional therapeutic immunosuppressant, has been used to control GVHD but, being non specific, it neither spares pre-existing donor memory cells nor discriminates between alloreactive and nonalloreactive donor T cells. Therefore, although GVHD can be controlled, it is at the cost of increased incidence of graft failure, leukaemia relapse and compromised immunity to post transplant infection, particularly to CMV. Further the researchers suggest that GVHD and/or immunosuppressant associated complications also prevent the application of allogenic HSCT amongst older patients and limit its wider use for the treatment of nonhematopoietic tumours, common non-malignant conditions like autoimmune disease, thalassemia, and immunodeficiencies and for gene replacement therapy. The paper puts forth an alternative strategy that primarily targets DC and also might prevent GVHD without the complications associated with T cell immunosuppression. This strategy includes depletion of APC including DC in mice with liposomal clodronate reduced development of liver GVHD, and UV radiation to deplete host skin DC prevented mouse skin GVHD. In addition, antibodies can be used to target specific c cells and some are available for therapeutic T cell depletion and immunosuppression. However, since there are no pan-DC – specific c antibodies therefore, it is not currently possible, to specifically deplete all human DC to achieve immunosuppression. Further, the activated DC are the prime stimulators of allogenic T cell proliferation in vitro and their depletion with antibody specifi c for CD83 or CMRF-44 antigen may significantly reduce the allogenic proliferative response, suggesting that such antibodies may have a role o play in controlling GVHD. The paper shows that treatment of MLC with anti-human CD83 antibody significantly reduced allogenic T cell proliferation but preserved pre-existing antiviral, particularly anti-CMV effectors/memory CD8 + T cells. In contrast, the therapeutic immunosuppressive antibody alemtuzumab (Campath-1H) prevented allergenic T cell proliferation by depleting virtually all cells including virus-specific T cells. The paper also shows that human DC is required to induce GVHD in the model used and that the treatment of the hu-SCID mice with CD83 antibody prevented GVHD yet allowed human leukocyte engraftment and preserved T cells, including CTL precursors specific for CMV, influenza, and the malignancy-associated antigen Mart1. Moreover, CD83 antibody treatment of hu-SCID mice did not impair in vivo induction of antileukemic cytolytic T cell effectors in response to immunization with human leukemic cell lines. The paper however also suggests a potential disadvantage of targeting CD83 along with DC for the prevention of GVHD in allogenic HSCT patients. According to the researchers DC may be required for the induction of GVL effectors from antileukemic precursors, be they T or NK cells. Reddy et al also showed in a mouse “acute leukaemia” model that the host and also the donor, though to a lesser extent, DC are required for effective GVL after allogenic HSCT, although the role of DC activation was not explored. Alternatively, the researchers suggest, that to retain peritransplant antileukemia priming by host CD83 + DC, antibody treatment might have to await the appearance of activated DC in the circulation after the transplant. This event normally precedes clinical GVHD. The researchers add that any significant improvement in the control of GVHD as a result of targeting DC may also allow wider utilization of allogenic HSCT for malignant conditions and for non-malignant conditions, which do not require GVL. The research data put forth in the paper provides compelling evidence that depletion of activated human DC is a promising alternative GVHD prevention strategy that warrants further investigation. A DC targeted therapy, which prevents alloreactive GVHD-inducing T cell generation, while allowing immature DC-mediated tolerance induction and preserving protective and therapeutic T cells, would also have wider applications in allotransplantation. The discussions initiated by the paper: The paper puts forward following points for discussion: Antibody specific for the DC activation marker CD83 is a potential new therapeutic option for the control of GVHD in alloHSCT. CD83 antibody not only limits the uncontrolled T cell proliferative response that characterizes GVHD but preserves the donor T cell repertoire. Current GVHD prophylaxis, be it ex vivo T cell depletion of the graft before transplant or non-specific immunosuppression, does not spare these vital components suppressants that target T cells, exemplified here by alemtuzumab and ATG, compromise post transplant immunity particularly to CMV and other infectious agents. T cell depletion also compromises the GVL effect and predisposes to recurrence of leukaemia. Theoretically, specific depletion of activated DC to control GVHD in clinical allogenic HSCT should preserve the antileukemia T cell repertoire. A potential disadvantage of targeting CD83 + DC for the prevention of GVHD in allogenic HSCT patients is that these DC may be required for the induction of GVL effectors from antileukemic precursors, be they T or NK cells. Nevertheless, if GVL proves to be compromised by peritransplant DC-targeted treatment, it could be managed by subsequent vaccination with leukaemia antigen-loaded donor DC or by donor leukocyte infusions, perhaps boosted by donor vaccination before transplantation. Alternatively, to retain peritransplant antileukemia priming by host CD83 + DC, antibody treatment might await the appearance, after transplant, of activated DC in the circulation, an event which precedes clinical GVHD. Similar researches in comparison with this paper The effectiveness of CD83 in preventing T cells from triggering GVHD has also been established by B. Turner et al. According to Turner, the central function of murine CD83 is to induce the progression of double-positive thymocytes to single CD4-positive T cells. Various lines of evidence prove that CD83 plays an additional role in the regulation of peripheral T and B cell responses. The research conducted by Turner et al. suggests that CD83 is released by the immature B cells and controls the further maturation and survival of the B cells. (B. Turenr, et al., 2006) A similar thought is put forth by Katja Lüthje et al. Their study suggests that reduction in the number of T cell effectively controls GVHD. In addition, the donor T cells are also required for graft versus leukemia (GVL), haematopoietic engraftment and protection from other infections. Very similar to the approach of David J Munster, et al. this study also reinforces the significant role of DC in GVHD. The researchers suggest that depletion in DC may prevent GVHD by preventing T cells from being sensitized to host antigens. The study hypothesized that the administration of DC-depleting antibodies could control GVHD. (Katja Lüthje1 et al. CD83 regulates splenic B cell maturation and peripheral B cell homeostasis) This study further substantiates the notion that T cell depletion also compromises the GVL effect and predisposes to recurrence of leukemia. Theoretically, specific depletion of activated DC to control GVHD in clinical alloHSCT should preserve the antileukemia T cell repertoire. In the study model of Katja Lüthje et al the transplant recipients were treated with monoclonal antibodies to reduce the DC before the transplant in MHC mismatched and miHA mismatched murine models of HSCT. No protection from GVHD was found in either model after using N418 monoclonal antibodies to reduce the DC. The same was found in the case of PDCA-1 mAb that targeted plasmacytoid DC. These observations parallel the efficacy of anti-human CD83 in our xenogeneic model of GVHD as presented by Munster et al. These results show that a targeting DC through antibody CD83 is a novel immunosuppressive agent that may be successful in preventing GVHD in allogeneic HSCT recipients and also substantiate the ongoing investigation. Another study conducted by leukemia research to prevent leukemia relapse after allogeneic hematopoietic stem cell transplantation (HSCT), indicated the chances of conducting a immunotherapy using donor CD8+ T cells that were generated by stimulating leukemic cell-derived dendritic or leukemic cell lysate pulsed donor cell-derived DCs (donor-DCs). In the study, the leukemic- and donor-DCs generated from mononuclear cells of patients and CD14+ cells of HLA-were checked against those of the donors, respectively. It was found that the expression of CD80, CD83, CD86, CD1a, and CD40 on leukemic-DCs was much lower than that on donor-DCs. Donor-DCs showed a higher capacity to initiate allogeneic T cells compared with leukemic-DCs. This study also indicated that leukemic- or donor-DCs pulsed with leukemic cell lysates can also be the prime donor cytotoxic T cells in vitro, and they may also be used as a potential alternative tool for treating leukemic patients who relapse after allogeneic HSCT. (Leukemia Research, Volume 28, Issue 5, Pages 517-524) GVHD is the most prominent risk involved in the allogeneic bone marrow transplantation. Till date, the reason or mechanism through which the allogeneic T cells get stimulated to initiate GVHD is unknown. In a murine allogeneic bone marrow transplantation model it was found that, the host-derived antigen-presenting cells were the primary culprits behind initiating GVHD. Thus, strategies for preventing graft versus host disease could be developed that are based on inactivating host antigen-presenting cells. These therapies would not only prevent GVHD but also enhance the success rate of allogeneic bone marrow transplantations conducted while treating the common genetic and neoplastic diseases. Similarly, in a model of CD8-dependent GVHD across MHC class I mismatch injection of allogeneic DCs, introduced extensive proliferation of donor CD8+ T cells and deterred GVHD resistance of chimeric recipients in which APCs were syngeneic to donors. These results demonstrate that DCs derived from the host are critical in stimulating donor CD4+ and CD8+ T cells to cause GVHD, and therefore, a selective targeting of host DCs may be a promising strategy to prevent GVHD. (B Turner. Et al, 2006)  Contradictory Researches: There are several contradictory researches to the hypothesis used by David J Munster et al. The first and the most prominent one question the role of T cells in triggering GVHD. A study conducted by Anderson Britt E, et al. for gauging the effects of donor T-cell trafficking and priming site on graft-versus-host disease induction by naive and memory phenotype CD4 T cells indicated that T cells do not cause GVHD but engraft and mount immune responses, including graft-versus-tumor effects. A plausible explanation for the inability of T cells to cause GVHD is that they lack CD62L and CCR7, which are instrumental in directing naive T cells to lymph nodes (LN) and Peyer patches (PP), putative sites of GVHD initiation. The researchers tested this hypothesis using T cells deficient in CD62L or CCR7, transplant recipients lacking PNAd ligands for CD62L, and recipients without LN and PP or LN, PP, and spleen. The results were astonishing. CD62L and CCR7 were not required for T cell mediated GVHD. Taken together, these data argue against the hypothesis that T (EM) fail to induce GVHD because of inefficient trafficking to LN and PP. The same is substantiated by another research that suggested that memory CD4+ T cells do not cause GVHD. The figure below presents the argument put forth in this research. (Source-http://www.jci.org/articles/view/17601/figure/1) Section III- Paper Analysis This section discusses the strengths and weaknesses of the paper in terms of the success rate or its hypothesis and the associated risk factors. Though there are contradictory researches that question the role of T cells in triggering GVHD, yet there are greater researches that prove their hand in causing GVHD. The hypothesis framework used by David J Munster et al. is a common and perhaps the most popular hypothesis used for developing a preventive therapy for GVHD. The hypotheses which states that antibody that targets activated DC could control GVHD while maintaining the protective T cell memory. Further, the paper cites evidence that human DC are required for GVHD in the chimeric human PBMC-transplanted SCID mouse model (hu-SCID) and that the anti-CD83 antibody treatment prevents GVHD and alters circulating human cytokine concentrations in the hu-SCID model. The effectiveness of CD83 in controlling GVHD has also been cited by another research that proposes Extracorporeal photopheresis (ECP) as a probable therapy for treating chronic graft-versus-host disease. This research suggests that photo activation of monocytes by ECP enhances their differentiation into CD83+ CD36+ dendritic cells which are again capable of phagocytosing the apoptotic T cells. In the presence of the co stimulatory molecules, B7.1 and B7.2, these dendritic cells are capable of presenting tumor antigens from phagocytosed tumor cells in the context of MHC molecules and thus initiating cellular immune responses. (F M Foss, et al., 2002) The plausible therapy put forth by the paper holds strong in terms of clinical evidence. The supremacy of CD83 antigens in reducing the harmful texture of T cells has been recurrently established by multiple researches. Immunologists have for years, studied the immune system to combat diseases that occur as an aftermath of an ongoing treatment. Several researches have established that the Dendritic cells (DCs), the most potent leukocytes for initiating cellular immunity, may be able to provide a solution to the challenges faced while conducting BMT for patients of leukaemia. In addition, an increased access to DCs in the recent years has led to a global realization of their potent immunostimulatory properties and numerous researchers have shown keen interest in using DCs as immune adjuvant for the treatment of human disease. In the same league, David J Munster et al also suggest that antibody specific for the DC activation marker CD83 is a potential new therapeutic option for the control of GVHD in alloHSCT. The in vitro and in vivo evidence of the research shows that CD83 antibody not only limits the uncontrolled T cell proliferative response that characterizes GVHD but preserves the donor T cell repertoire, in particular, potentially life saving antiviral memory T cells and antileukemic effectors. Though the paper does not suggest any potential solution to the disadvantage associated with targeting CD83 + DC for the prevention of GVHD in allogenic HSCT patients, yet is succeeds in establishing antibody to the dendritic cell surface activation antigen CD83 as a potential clinical therapy for preventing GVHD. The paper further provides substantial evidence that any significant improvement in the control of GVHD as a result of targeting DC may enable wider utilization of allogenic HSCT for preventing malignant conditions, without requiring GVL. The research data proves that depletion of activated human DC is a promising alternative GVHD prevention strategy that warrants further investigation. Further, it cannot be ignored that the success depicted in the paper is based on trials conducted on mice and rabbits. Whether the same therapy will translate into a successful treatment for humans cannot be predicted. In the past two decades, several researches have brought forth successful experiments pertaining to GVHD on mice. However, their success rate on humans has been meagre. Only future investigations involving a human model may be able to predict the success quotient of the CD83 antigen in controlling GVHD. Section IV-Future aspects of this treatment This section concludes the review and discusses the plausible future course for treatments of GVHD involving CD83 Champlin R. in graft-versus-leukemia without graft-versus-host disease: an elusive goal of bone marrow transplantation Semin Hematol. 1992; 29: 46, suggests that the ideal target antigens used for preventing GVHD should contain the following three qualities: The target antigens must be: Hematopoietic system specific Functionally membrane expressed Immunogenic Further, the role of DCs in combating infections that arise as an aftermath of an ongoing treatment has been discussed above. Collating the two facts, it can be well established that CD83 remains the best available marker of terminally matured DCs, and it is never expressed by committed macrophages. Moreover, several recent reports have shown that transplant related mortality has gradually decreased in the last two decades owing to significant changes made while handling allogenioc HSCT and allogenci SCT. Along with further investigations to develop a clinical therapy or a drug that uses antigen CD83 and DCs to prevent GVHD, the following factors may also be considered while dealing with GVHD: 1) Using improved prevention and treatment of GVHD by cyclosporine and methotrexate and possibly by mycophenolate mofetil 2) Transplantation of a higher hematopoietic progenitor cell dose 3) Implementing molecular monitoring of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) and the subsequent pre-emptive treatment of patients with viral reactivation; 4) Installing improved detection and therapy of fungal infections 5) Introducing high-resolution typing for HLA matching and the increased number of potential unrelated donors 6) Appreciating number of pretransplant and procedure-related factors that affect outcome, which allow risk assessment, and thereby may guide transplant policies 7) Use of alternative therapies like ECP The widespread application of allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of hematological malignancies and other diseases is restricted by the poor availability of suitable donors. In addition, significant barriers to successful major histocompatibility complex (MHC) mismatched HSCT include the increased risk of graft failure and the possible induction of severe and refractory acute and/or chronic GVHD. Even in a case when the immune response is controlled through use of immunosuppressant, successfully engrafted recipients that are free from active GVHD, a delayed immune reconstitution and an increased vulnerability towards the fatal infection has been seen. Further, prolonged suppression of the host immune response can also lead to an increased risk of leukemic relapse. Over the years, various researches have demonstrated that T cells are the principal orchestrators of both GVHD and GVL. However, the mechanisms of GVHD induction are not yet fully elucidated. Also, it is well established that GVHD primarily involves skin, gut, liver, and perhaps lung. A successful outcome of HSCT involves engraftment, prevention of GVHD, eradication of leukemia, and immune reconstitution. Since GVHD and GVL are closely linked; the severity of GVHD is inversely correlated with the probability of a relapse after allogeneic HSCT.97. Currently, several strategies are being developed to separate GVHD from GVL activity. While most efforts are being focused on the identification of GVHD-specific and tumor-specific antigens, the role of T cells in triggering both GVHD and GVL has been well established. It is clear that GVHD is a complex process that is unlikely to be controllable with a single agent. Various encouraging studies of single-cytokine inhibition in mouse models have not translated well to human trials. Most studies show that partial benefits can occur through a variety of approaches, including T cell depletion, immunophilin inhibition, cytokine inhibition, manipulation of costimulation, and the use of antiproliferative agents, but these interventions are rarely used synergistically. A useful strategy will be to attempt to control GVHD by recognizing the underlying path physiology and interfering with disparate steps along the pathway; for instance, maintaining gut integrity, preventing cytokine up regulation by endotoxin, and interfering with T cell activation. If interventions are chosen wisely, it may be possible to control the inflammatory aspect of GVHD while sparing the critically important antileukemic effect. (Joseph H. Antin, 2001) References: 1) (http://www.articlebase.info/Article/All-Bones-About-It--New-Treatment-For-GVHD/4614 2) (http://www.wdxcyber.com/gvhd.html) 3) A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukaemia responses. ,Reddy , P. , Y. Maeda , C. Liu , O.I. Krijanovski , R. Korngold , andJ.L. Ferrara . 2005Nat. Med. 11 : 1244 – 1249 . 4) Acute graft-versus-host disease: inflammation run amok?, Joseph H. Antin 5) Bone Marrow Transplantation (2008) 41, 887–893; doi:10.1038/sj.bmt.1705987; published online 21 January 2008 6) CD83 regulates splenic B cell maturation and peripheral B cell homeostasis, Katja Lüthje1, Birte Kretschmer1, Bernhard Fleischer1,2 and Minka Breloer 7) Clinical manifestations of graft-versus-host disease in recipients of marrow from HLA-matched sibling donors. Glucksberg, H, et al Transplantation 1974. 18:295-304. 8) Effects of donor T-cell trafficking and priming site on graft-versus-host disease induction by naive and memory phenotype CD4 T cells,Anderson Britt E; Taylor Patricia A; McNiff Jennifer M; Jain Dhanpat; Demetris Anthony J; Panoskaltsis-Mortari Angela; Ager Ann; Blazar Bruce R; Shlomchik Warren D; Shlomchik Mark J,Blood 2008;111(10):5242-51 9) Evidence that sustained growth suppression of intestinal anaerobic bacteria reduces the risk of acute graft-versus-host disease after sibling marrow transplantation. Beelen, DW, et al. Blood 1992. 80:2668-2676. 10) Extracorporeal photopheresis in chronic graft-versus-host disease, F M Foss, G Gorgun and K B Miller, 2002) 11) Graft versus host disease (GVHD) is a major limitation of allogeneic hematopoietic stem cell transplantation (HSCT). 12) Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Storb, R, et al. Beneficial effects of a protective environment. N Engl J Med 1983. 308:302-307. 13) Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function. Kuroiwa, T, et al. J Clin Invest 2001. 107:1365-1374. 14) High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution. Chakrabarti , S. , S. Mackinnon , R. Chopra , P.D. Kottaridis , K. Peggs , P. O ’ Gorman , R. Chakraverty , T. Marshall , H. Osman , P. Mahendra , et al . 2002 .Blood . 99 : 4357 – 4363 . 15) Host dendritic cells alone are suffi cient to initiate acute graft-versus-host disease. J. Immunol. Duff ner , U.A. , Y. Maeda , K.R. Cooke , P. Reddy , R. Ordemann , C. Liu , J.L. Ferrara , and T. Teshima . 2004 172 : 7393 – 7398 . 16) Host Dendritic Cells Alone Are Sufficient to Initiate Acute Graft-versus-Host Disease1 17) Hostreactive CD8+ memory stem cells in graft-versus-host disease. Zhang , Y. , G. Joe , E. Hexner , J. Zhu , and S.G. Emerson . 2005 . 18) http://igrid-ext.cryst.bbk.ac.uk/WWW/PhD_thesis_files/image032.jpg 19) Hyperacute GVHD: risk factors, outcomes, and clinical implications by: Rima M Saliba, Marcos de Lima, Sergio Giralt, Borje Andersson, Issa F Khouri, Chitra Hosing, Shubhra Ghosh, Joyce Neumann, Yvonne Hsu, Jorge De Jesus, Muzaffar H Qazilbash, Richard E Champlin, Daniel R Couriel, 2007 20) Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu. Rev. Immunol. Welniak , L.A. , B.R. Blazar , and W.J. Murphy . 2007, 25 : 139 – 170 . 21) Immunotherapeutic Applications of Dendritic Cells, James W. Young, M.D.* 22) LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. Cooke, KR, et al J Clin Invest 2001. 107:1581-1589. 23) Prevention of Graft Versus Host Disease by Inactivation of Host Antigen-Presenting Cells , Warren D. Shlomchik, 1 Matthew S. Couzens, 1 Cheng Bi Tang, 1 Jennifer McNiff, 3 Marie E. Robert, 4 Jinli Liu, 56 Mark J. Shlomchik, 56* Stephen G. Emerson 12* 24) Prevention of graft versus host disease by inactivation of host antigen-presenting cells . Science , Shlomchik , W.D. , M.S. Couzens , C.B. Tang , J. McNiff , M.E. Robert ,J. Liu , M.J. Shlomchik , and S.G. Emerson . 1999 285 : 412 – 415 . 25) Targeting CD83 delays GvHD onset in murine allogeneic haematopoietic stem cell transplant recipients, B. Turner, L. Sinfield, M. Kambouris, H. Cullup, J. Wilson, A. Palkova, D. Hart, D. Munster, A. Rice (Newcastle, UK; South Brisbane, AU) 26) Transfusion Medicine: New Clinical Applications of Cellular Immunotherapy, Malcolm Brenner, (Chair), Claudia Rossig, Uluhan Sili, James W. Young and Els Goulmy 27) Ulrich A. Duffner, Yoshinobu Maeda, Kenneth R. Cooke, Pavan Reddy, Rainer Ordemann, Chen Liu, James L. M. Ferrara, and Takanori Teshima2 Read More