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Transplantation immunology (part II)

Transplantation immunology (part II)

Presented by Rapisa Nantanee, MD.

March19, 2021

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Transplantation immunology (part II)

  1. 1. Transplantation Immunology Part II Topic Review March 19th, 2021 Rapisa Nantanee, M.D. Pediatric Allergy and Immunology Unit King Chulalongkorn Memorial Hospital
  2. 2. Hematopoietic Stem Cell (HSC) Transplantation • Indications, Methods, and Immune Barriers in Hematopoietic Stem Cell Transplantation • Immunologic Complication of Hematopoietic Stem Cell Transplantation A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  3. 3. Hematopoietic Stem Cell (HSC) Transplantation • Involves the treatment of recipients with irradiation and/or chemotherapy followed by the infusion of cells containing haematopoietic stem and progenitor cells with or without immune cells, including T cells, B cells and natural killer (NK) cells. • Obtained from: • Bone marrow • Cytokine-mobilized peripheral blood • Treatment with granulocyte colony-stimulating factor and/or a stromal cell-derived factor 1 inhibitor to mobilize haematopoietic stem and progenitor cells from the marrow to the circulation, where they can be collected by leukapheresis for use in transplantation. • Umbilical cord blood (UCB) • Blood that is collected from the umbilical cord after childbirth and is used as a source of haematopoietic stem cells to treat patients with haematological disorders. • One unit of cord blood refers to blood harvested from one umbilical cord. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  4. 4. Hematopoietic Stem Cell (HSC) Transplantation • Indications • Leukemias and pre-leukemic conditions • Only curative treatment for CLL and CML • Graft-versus-tumor effect: mature T cells and NK cells present in the bone marrow or stem cell inoculum recognize alloantigens on residual tumor cells and destroys them. • Diseases caused by inherited mutations in genes affecting only cells derived from HSCs, such as lymphocytes or red blood cells. • Examples: adenosine deaminase (ADA) deficiency, X-linked severe combined immunodeficiency disease, and hemoglobin mutations, such as beta-thalassemia major and sickle cell disease A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  5. 5. Bonilla FA, et al. J Allergy Clin Immunol. 2015 Nov;136(5):1186-205.e1-78.
  6. 6. Bonilla FA, et al. J Allergy Clin Immunol. 2015 Nov;136(5):1186-205.e1-78.
  7. 7. Bonilla FA, et al. J Allergy Clin Immunol. 2015 Nov;136(5):1186-205.e1-78.
  8. 8. Hematopoietic Stem Cell (HSC) Transplantation • Immune Barriers • Allogeneic HSCs are rejected by even a minimally immunocompetent host, and therefore, the donor and recipient must be carefully matched at all MHC loci. • In addition to adaptive immune mechanisms, HSCs may be rejected by NK cells. • Hybrid resistance: Irradiated F1 hybrid mice reject bone marrow cells donated by either inbred parent. • Probably due to host NK cells reacting against bone marrow precursors that lack class I MHC molecules expressed by the host. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  9. 9. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 4.
  10. 10. Hematopoietic Stem Cell (HSC) Transplantation • Immune Barriers • Even after successful engraftment, two additional problems are frequently associated with HSC transplantation: • GVHD • Immunodeficiency A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  11. 11. Hematopoietic Stem Cell (HSC) Transplantation • Immunologic Complication of Hematopoietic Stem Cell Transplantation • Graft-Versus-Host Disease • Acute GVHD • Chronic GVHD • Immunodeficiency After Hematopoietic Stem Cell Transplantation A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  12. 12. Hematopoietic Stem Cell (HSC) Transplantation: Immunologic Complication • Graft-Versus-Host Disease • Caused by the reaction of grafted mature T cells in the HSC inoculum with alloantigens of the host. • It occurs when the host is immunocompromised and therefore unable to reject the allogeneic cells in the graft. • In most cases, the reaction is directed against minor histocompatibility antigens of the host. • Because bone marrow transplantation is not usually performed when the donor and recipient have differences in MHC molecules. • GVHD may also develop when solid organs that contain significant numbers of T cells are transplanted, such as the small bowel, lung, or liver. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  13. 13. Hematopoietic Stem Cell (HSC) Transplantation: Immunologic Complication • Graft-Versus-Host Disease • Principal cause of mortality among HSC transplant recipients. • GVHD prophylaxis • Immediately after HSC transplantation, immunosuppressive agents are given. • Including the calcineurin inhibitors cyclosporine and tacrolimus, antimetabolites such as methotrexate, and the mTOR inhibitor sirolimus. • Classified on the basis of histologic patterns into acute and chronic forms. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  14. 14. Hematopoietic Stem Cell (HSC) Transplantation: Immunologic Complication • Graft-Versus-Host Disease • Acute GVHD • Characterized by epithelial cell death in the skin, liver (mainly the biliary epithelium), and gastrointestinal tract. • Rash, jaundice, diarrhea, and gastrointestinal hemorrhage • When the epithelial cell death is extensive, the skin or the lining of the gut may slough off - acute GVHD may be fatal. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  15. 15. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  16. 16. Hematopoietic Stem Cell (HSC) Transplantation: Immunologic Complication • Graft-Versus-Host Disease • Acute GVHD • Initiated by mature T cells transferred with HSCs. • Elimination of mature donor T cells from the graft can prevent the development of GVHD. • Also decreased the graft-versus-leukemia effect. • T cell–depleted HSC preparations also tend to engraft poorly, perhaps because mature T cells produce colony-stimulating factors that aid in stem cell repopulation. • NK cells, CD8+ CTLs and cytokines A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  17. 17. Hematopoietic Stem Cell (HSC) Transplantation: Immunologic Complication • Graft-Versus-Host Disease • Chronic GVHD • Characterized by fibrosis and atrophy of one or more of the same organs, without evidence of acute cell death. • May also involve the lungs and produce bronchiolitis obliterans (obliteration of small airways), similar to what is seen in chronic rejection of lung allografts. • When it is severe, chronic GVHD leads to complete dysfunction of the affected organ. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  18. 18. Hematopoietic Stem Cell (HSC) Transplantation: Immunologic Complication • Graft-Versus-Host Disease • The relationship of chronic GVHD to acute GVHD • Not known • Chronic GVHD may represent the fibrosis of wound healing secondary to acute loss of epithelial cells. • Chronic GVHD can arise without evidence of prior acute GVHD. • An alternative explanation is that chronic GVHD represents a response to ischemia caused by vascular injury. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  19. 19. Hematopoietic Stem Cell (HSC) Transplantation: Immunologic Complication • Graft-Versus-Host Disease • Treatment • Intense immunosuppression such as high doses of steroids • Therapeutic failures may be because these treatments target only some of many effector mechanisms at play in GVHD, and some treatments may deplete Tregs, which are important for preventing GVHD. • Experimental therapies • Anti-TNF antibodies and Treg transfer. • Tumor antigen-specific adoptive T cell therapy: HSC preparations rigorously depleted of mature T cells and NK cells to reduce the risk of GVHD, combined with specific effective antileukemia T cells. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  20. 20. Hematopoietic Stem Cell (HSC) Transplantation: Immunologic Complication • Immunodeficiency • HSC transplantation is often accompanied by clinical immunodeficiency. • The transplant recipients may be unable to regenerate a complete new lymphocyte repertoire. • Radiation therapy and chemotherapy used to prepare recipients for transplantation may deplete the patient’s memory cells and long-lived plasma cells, and it can take a long time to regenerate these populations. • Susceptible to viral infections, especially CMV, and to many bacterial and fungal infections, Epstein-Barr virus–provoked B cell lymphomas • Prophylactic antibiotics, antiviral prophylaxis to prevent CMV infections, antifungal prophylaxis to prevent invasive Aspergillus infection, and maintenance IVIG infusions. • Immunized against common infections. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  21. 21. Hematopoietic Stem Cell (HSC) Transplantation • GVHD is potentiated by conditioning-induced inflammation. • Enhances the effector functions of donor T cells and facilitates the infiltration of activated donor T cells to the GVHD target tissues. • In the past 20 years, HCT has been increasingly performed using reduced intensity or non-myeloablative conditioning regimens. • ‘Non-myeloablative conditioning’ - conditioning that leaves sufficient recipient haematopoiesis in place to avoid lethal failure of the bone marrow in the absence of a replacement haematopoietic graft. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  22. 22. Hematopoietic Stem Cell (HSC) Transplantation • HCT, on the basis of the source of haematopoietic cells, categorized into: • Autologous • The infused haematopoietic cells are from the patients themselves. • Allogeneic • Transplants between individuals of the same species. • Mismatched MHC or minor histocompatibility antigens exist between the donor and the host, and this can elicit an immune response, which results in either graft rejection or graft-versus-host disease. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  23. 23. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  24. 24. Alternative donors for HCT • HLA-matched siblings - the first-choice donors for HCT • HLA-matched unrelated donor • If an appropriate unrelated donor cannot be found: • HLA-mismatched unrelated donors • UCB • Related haploidentical donors • A haploidentical donor is matched for half of the MHC alleles of the recipient (one HLA haplotype). The donor can be the patient’s parents, siblings, children or other relatives. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  25. 25. Alternative donors for HCT: UCB transplantation • Associated with a decreased incidence of GVHD compared to bone marrow transplantation, even in the presence of a greater degree of HLA mismatching. • The immaturity of neonatal T cells may be partially responsible. • CD4+ T cells from UCB showed defective activation and differentiation in response to alloantigen stimulation. • Concentrations of TReg cells are higher in UCB than in adult blood. • Dendritic cells from UCB demonstrated a more immature phenotype characterized by lower expression of MHC class II and co-stimulatory molecules. They are less able to promote T helper 1 (TH1) cell differentiation and instead induce the generation of TReg cells. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  26. 26. Alternative donors for HCT: UCB transplantation • Limited number of stem cells • The number of CD34+ cells from one unit of UCB is about one-tenth of that in a bone marrow graft and 1/20–1/30 of that in a cytokine-mobilized peripheral blood graft. • Decreased engraftment and delayed immune reconstitution. • This problem may be solved by • Using UCB from two different donors • Preserve GVT effects and enhance immune reconstitution. • Ex vivo-expanded stem cells from one unit of cord blood together with another unit of unexpanded cord blood • Injection of haematopoietic cells directly into bone marrow • One unit of UCB and haploidentical haematopoietic cells • Unknown how this approach may affect immune reconstitution and GVT effects after UCB transplantation. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  27. 27. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16. - Although a single unit of umbilical cord blood (UCB) graft can be used for haematopoietic cell transplantation (HCT), the limited number of haematopoietic stem cells (HSCs) is often associated with delayed engraftment and immune reconstitution. - Engraftment can be enhanced by the addition of a second unit of UCB, or by the addition of ex vivo-expanded HSCs from another unit of UCB or from a haploidentical adult haematopoietic donor graft.
  28. 28. Alternative donors for HCT: Haploidentical transplantation • HLA disparities are associated with increased GVHD, graft rejection and poor immune reconstitution. • The number of CD34+ cells in the donor graft is an important factor in determining the success of the engraftment. • Depleting T cells and B cells using anti-CD3 and anti-CD19 microbeads. • Preserve HSCs within the CD34– cell population and other cell types that may facilitate the engraftment of donor grafts. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  29. 29. Alternative donors for HCT: Haploidentical transplantation • NK cells have a role in GVT effects. • The use of donors whose NK cells expressed killer-cell immunoglobulin-like receptors (KIRs) that did not recognize (and could therefore not be inhibited by) the patients’ MHC class I molecules was associated with markedly decreased relapse rates and improved survival rates in AML. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  30. 30. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16. Haploidentical grafts can be derived from the patient’s parents, siblings or children (or other relatives). - T cell depletion may be performed to prevent graft-versus-host disease (GVHD), and/or donor-derived ex vivo- expanded mesenchymal stem cells may be added to the grafts to enhance engraftment and/or to prevent GVHD.
  31. 31. Reduced intensity conditioning • Originally, myeloablative conditioning was used to maximize the killing of leukaemia cells before HCT, which was used as a rescue therapy for the haematopoietic destruction caused by the cancer therapy. • The toxicity of myeloablative conditioning causes morbidity and mortality. • Increased GVHD risk - increased inflammation and disruption of mucosal barriers, allowing entry of pro-inflammatory microorganisms into the underlying recipient tissues. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  32. 32. Reduced intensity conditioning • Enables these patients to undergo HCT. • Older patients or in patients who have active disease, have failed multiple or combined treatments, or have organ damage. • GVHD has not been markedly reduced. • Perhaps owing in part to the increased susceptibility of older patients • Tumour control may be achieved by GVT effects of donor T cells contained in the initial donor grafts or by T cells administered in donor leukocyte infusions (DLIs). • Haploidentical and UCB transplantation HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  33. 33. Reduced intensity conditioning • Enrichment of host natural killer T (NKT) cells induces an IL-4-dependent expansion of donor TReg cells. • In association with TH2-type polarization of donor T cells. • The Stanford group developed a fractionated total lymphoid irradiation and ATG-mediated T cell depletion protocol in order to reduce the incidence of GVHD. • Associated with a very low incidence of GVHD in HLA-identical allogeneic HCT, with apparently preserved GVT effects. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  34. 34. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  35. 35. Enhancing immune reconstitution • HCT can be associated with prolonged immunodeficiency post- transplantation. • Especially after extensive treatment for underlying malignancies and the use of T cell- depleted grafts. • Considerable time (about 1–2 years) is needed for the complete regeneration of the T cell and B cell compartments, especially when the thymus has lost most of its function owing to age or prior therapies. • GVHD and the immunosuppressive drugs used for its prevention can also severely delay immune reconstitution. • During this time, patients are subject to opportunistic infections. • Effective approaches to hastening immune reconstitution following transplantation are needed. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  36. 36. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16. - Allodepletion refers to the specific removal of anti-recipient alloreactive T cells from the donor graft. - Restoring the broad T cell repertoire and thus immunity to infectious pathogens without inducing GVHD. - To generate allodepleted donor T cells for transfer, donor T cells are activated by host antigen-presenting cells (APCs), followed by treatment with toxin-conjugated antibodies against activation markers, such as CD25, CD69, CD71 or CD134, or treatment with antibodies in combination with magnetic separation. - Potential limitations: unsynchronized expression of activation markers, stimulation of only immunodominant clones in alloreactivity assays and failure of a single activation marker to identify all alloreactive T cells. - Improved immunocompetence, but GVHD is still a major problem.
  37. 37. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16. - Pathogen-specific T cells must first be isolated and are then expanded ex vivo before infusion to haematopoietic cell transplantation (HCT) recipients. - Restore immunity to Epstein–Barr virus (EBV), cytomegalovirus and adenovirus infections following HCT. - The cumbersome isolation and expansion processes, which require special expertise, and the fact that immunity can only be restored to selected infectious agents currently limit the general applicability of the approach. - Third-party allogeneic EBV-specific T cells could also be used when HCT donor-derived T cells are not available, as in UCB transplantation. Immune responses of the recipients to these cells may limit their survival.
  38. 38. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16. - A decreased number of lymphoid progenitor cells accessing the thymus can limit T cell reconstitution, and the addition of T cell progenitors to the donor graft has been shown to enhance immune reconstitution following experimental allogeneic HCT. - Donor-derived T cell progenitor cells can be generated in vitro by co-culture of donor haematopoietic stem cells (HSCs) with a stromal cell line expressing δ-like-1 (DL1), which is a ligand of NOTCH1. Stem cells will differentiate into T cell progenitor cells and are expanded in number. The T cell progenitor cells are then infused to HCT recipients. - Also enhanced GVT effects without inducing GVHD.
  39. 39. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16. - To allow for control of graft-versus-host disease (GVHD) induced by donor T cells given to enhance the immune reconstitution of HCT recipients, donor T cells are first transduced with a suicide gene that enables the cells to be killed by exogenous agents interacting with the transduced gene product. - The suicide gene-transduced donor T cells are infused to HCT recipients. - When GVHD arises, the transduced donor T cells are induced to die so that GVHD can be controlled. A small number of transduced donor T cells will survive.
  40. 40. Enhancing immune reconstitution • Use of biological agents • Several categories of exogenous factors have been shown to enhance immune reconstitution in animal models. • These factors include cytokines (such as IL-7), agents blocking sex hormones, and keratinocyte growth factor (KGF; also known as FGF7). HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  41. 41. Graft-versus-host disease (GVHD) • Fatal to approximately 15% of transplant recipients. • Results from immunological attack on target recipient organs or tissues (such as the skin, liver and gut) by donor allogeneic T cells that are transferred along with the allograft. • The development and severity of GVHD depends on factors such as • Recipient age, toxicity of the conditioning regimen, haematopoietic graft source and GVHD prophylaxis approaches. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  42. 42. Graft-versus-host disease (GVHD) • Chronic GVHD • Originally defined as occurring after the first 100 days post-HSCT. • Now known to have a characteristic clinical presentation, which resembles autoimmune vascular diseases and is distinct from acute GVHD. • Occurs in 30–65% of allogeneic HSCT recipients. • Can be highly debilitating in its extensive form. • 5-year mortality rate of 30–50% that is mainly due to immune dysregulation and opportunistic infections. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  43. 43. Overview of GVHD pathogenesis • Defined as a syndrome in which donor immunocompetent cells recognize and attack host tissues in immunocompromised allogeneic recipients. • Acute GVHD and chronic GVHD involve distinct pathological processes. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  44. 44. Overview of GVHD pathogenesis Acute GVHD Chronic GVHD Strong inflammatory components More autoimmune and fibrotic features Driven mainly by TH1- and TH17-type responses Predominately mediated by TH2-type responses - Alloreactive donor T cell-mediated cytotoxic responses against the tissues of the recipient, mediated by cell-surface and secreted factors - Tissue damage caused by the cytotoxic T cells leads to the recruitment of other effector cells (including natural killer (NK) cells and neutrophils), which further augment tissue injury and result in a self-perpetuating state of GVHD that is difficult to control once it is fully initiated. - 6 hallmarks: 1. Damage to the thymus 2. Decreased negative selection of alloreactive CD4+ T cells 3. Immune deviation to a TH2-type cytokine response 4. Activation of macrophages that produce PDGF and TGFβ1 5. Low numbers of TReg cells 6. B cell dysregulation - Occur in almost any organ but mainly affect oral and ocular mucosal surfaces and the skin, lungs, kidneys, liver and gut. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  45. 45. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58. Acute GVHD
  46. 46. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58. Chronic GVHD
  47. 47. Role of innate immune responses • Current data implicate the innate immune response as being responsible for initiating or amplifying acute GVHD. • Molecules such as bacterial lipopolysaccharide (LPS) that are released from the injured gut during the conditioning regimen activate innate immune receptors, including Toll-like receptors (TLRs), and cause a cytokine storm, which favours the development of acute GVHD. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  48. 48. Role of innate immune responses • Damage-associated molecular patterns (DAMPs), which are released following conditioning regimen-induced tissue damage, may have a role in the induction of GVHD. • Dying cells in the guts of mice and the peritoneal fluid of patients with GVHD release ATP, which binds to its receptor P2X7 on host APCs and activates the inflammasome. • Leads to upregulation of the expression of co-stimulatory molecules by APCs. • Pharmacological blockade of P2X7 decreases the incidence of acute GVHD and increases the number of TReg cells. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  49. 49. Role of APCs • The presentation of minor histocompatibility antigens by MHC class I molecules on recipient haematopoietic APCs is important, although not required, for CD8+ T cell-dependent acute GVHD. • Donor APCs can augment this response. • Parenchymal tissue cells can acquire APC functions and have been shown to promote marked expansion of alloreactive donor T cell populations in the gastrointestinal tract. • In the absence of functional host haematopoietic APCs, the presentation of minor histocompatibility antigens by donor haematopoietic APCs or host non-haematopoietic APCs is sufficient for GVHD induction. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  50. 50. Targeting B cells • Acute GVHD • Incorporating rituximab — a CD20-specific monoclonal antibody that depletes B cells — into the conditioning regimen reduces the incidence and severity of acute GVHD. • An association between high numbers of donor B cells and the development of both acute and chronic GVHD. • Paradoxically, B cells can also have a protective role in GVHD • By controlling the differentiation of naïve T cells into effector T cells and by inhibiting the proliferation of alloantigen-specific effector T cells, mediated through the secretion of IL-10 and the induction of alloantigen-specific TReg cells by B cells. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  51. 51. Targeting B cells • Chronic GVHD • Important role for B cell dysregulation in chronic GVHD pathogenesis and treatment. • Targeting germinal centre formation (using lymphotoxin-β receptor blocking agents) and inhibiting the IL-17–BAFF (B cell-activating factor) axis, which is a cause of B cell dysregulation, are particularly interesting strategies for future clinical intervention(s) in chronic GVHD and are worthy of investigation. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  52. 52. Targeting T cell responses • Both donor CD4+ and donor CD8+ T cells have crucial roles in the pathogenesis of GVHD. • GVHD is a result of naive T cell responses. • Owing to their ability to differentiate into various effector T cell subsets — namely, TH1 cells, TH2 cells and TH17 cells — CD4+ T cells are particularly important in the initiation of GVHD in mice and have been considered as potential targets for the treatment and prevention of GVHD in the clinic. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  53. 53. Targeting T cell responses • TH1 and TH2 cell responses • TH1 cells and proinflammatory molecules such as IL-1, IL-6, IL-12, TNF and nitric oxide have been shown to be aetiological factors in the induction of GVHD. • The impact of IFNγ on acute GVHD may depend on the timing of its production, as IFNγ can have • Immunosuppressive effects when it is present immediately after HSCT but • Exacerbate disease via its pro-inflammatory properties at later stages. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  54. 54. Targeting T cell responses • TH1 and TH2 cell responses • TH2-type cytokines, such as IL-4, can reduce acute GVHD, their effects may depend on timing. • Owing to the paradoxical and variable effects of targeting TH1- and TH2-type cytokines, such approaches alone will probably not be sufficient to prevent acute GVHD, but they may serve as adjunct strategies to reduce the issue injury of GVHD. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  55. 55. Targeting T cell responses • TH17 cell responses • TH17 cells: production of IL-17A, IL-17F, IL-21 and IL-22. • Initial studies reported that a lack of donor TH17 cells augmented TH1 cell differentiation and exacerbated acute GVHD. • An absence of IL-17 production by donor cells markedly impairs the development of CD4+ T cell-mediated acute GVHD. • TH17 cells are sufficient but not necessary to induce GVHD. • In patients with acute GVHD, IL-17-producing cells can be found in biopsy samples from the gut but not from the skin. • Thus, IL-17 may yet prove to be a viable target for neutralization in patients with GVHD in the gut. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  56. 56. Targeting T cell responses • TH17 cell responses • IL-21 is another potential neutralization target. • Its role in promoting the activation, differentiation, maturation or expansion of NK cell, B cell, T cell and APC populations. • Antitumour effects and can facilitate autoimmunity. • Increases TH17 cell activity not only by directly augmenting TH17 cell responses but also by inhibiting TReg cells. • Inhibition of IL-21–IL-21 receptor signalling in vivo reduced acute GVHD activity in the gut, and this effect was associated with decreased TH1 cell and increased TReg cell numbers in the gut mucosa. • A similar outcome was observed using a neutralizing antibody specific for human IL-21 in a human-into-mouse xenogeneic model of gut GVHD. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  57. 57. Targeting T cell responses • TH17 cell responses • Cytokines involved in the induction of TH17 cells, such as IL-6. • Together with TGFβ, IL-6 promotes the differentiation of naive T cells into TH17 cells, whereas in its absence TReg cells are induced. • High serum levels of IL-6 can be predictive of severe acute GVHD. • IL-6 gene polymorphisms are associated with acute GVHD and chronic GVHD in patients. • Infusion of an IL-6 receptor-specific monoclonal antibody in a model of acute GVHD led to increased TReg cell numbers and a reduction in GVHD pathological damage, particularly in the gut. • IL-6 inhibition may have more pronounced effects in chronic GVHD. • A direct relationship between IL6 polymorphism and chronic GVHD has been demonstrated and the effects of IL-6-induced TH17 cells on B cell dysregulation are a hallmark of chronic GVHD. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  58. 58. Targeting T cell responses • TH17 cell responses • IL-23: survival and proliferation of TH17 cells • A member of the IL-12 family • The cytokines of this family have shared subunits and a common downstream signalling pathway mediated by STAT4. • In mice, the infusion of IL-23-deficient splenocytes, or the use of an antibody specific for the p19 subunit of IL-23, decreased GVHD-associated morbidity, while preserving GVT responses. • Neutralizing IL-12 can also be an effective means of preventing acute GVHD. • However, administration of high doses of IL-12 at early but not later time points following HSCT protects mice from acute GVHD via an IFNγ-dependent mechanism. • Targeting the IL-12–IL-23 axis might be beneficial in patients with refractory acute GVHD. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  59. 59. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  60. 60. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  61. 61. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  62. 62. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  63. 63. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  64. 64. Blazar BR, Murphy WJ, Abedi M. Nat Rev Immunol. 2012 May 11;12(6):443-58.
  65. 65. Minor histocompatibility antigens • Minor histocompatibility (H) antigens are T-cell epitopes derived from polymorphic proteins. • Minor H peptides are presented by various major histocompatibility complex (MHC) class I and class II molecules. • The MHC/minor H peptide complexes can act as transplantation barriers in allogeneic human leukocyte antigen (HLA)-matched hematopoietic stem-cell transplantation (HSCT) and in solid-organ transplantation. E. Spierings. Tissue Antigens, 2014, 84, 347–360.
  66. 66. Minor histocompatibility antigens • Minor histocompatibility (H) antigens are T-cell epitopes derived from polymorphic proteins. • Minor H peptides are presented by various major histocompatibility complex (MHC) class I and class II molecules. • The MHC/minor H peptide complexes can act as transplantation barriers in allogeneic human leukocyte antigen (HLA)-matched hematopoietic stem-cell transplantation (HSCT) and in solid-organ transplantation. E. Spierings. Tissue Antigens, 2014, 84, 347–360.
  67. 67. E. Spierings. Tissue Antigens, 2014, 84, 347–360.
  68. 68. Minor histocompatibility antigens • The most common form of genetic polymorphism leading to minor H antigens, is the nonsynonymous single nucleotide polymorphism (SNP). • These SNPs consist of a single nucleotide difference in the genome that results in a different amino acid in the peptide. E. Spierings. Tissue Antigens, 2014, 84, 347–360.
  69. 69. Minor histocompatibility antigens • Hematopoietic stem-cell transplantation • Minor H antigen mismatching has clinically been associated with an increased risk of GvHD and an improved graft-versus-leukemia (GvL) effect. • The participation of the minor H antigens in GvHD and GvL reactions is related to their cell and tissue expression; • Hematopoietic system-restricted minor H antigens might be able to enhance immune responses in GvL. • Broadly expressed minor H antigens are supposed to contribute to both GvHD and GvL. E. Spierings. Tissue Antigens, 2014, 84, 347–360.
  70. 70. E. Spierings. Tissue Antigens, 2014, 84, 347–360.
  71. 71. E. Spierings. Tissue Antigens, 2014, 84, 347–360.
  72. 72. Future perspectives • HCT is a fast-evolving cellular therapy. • Substantial progress has been made in the field, including new applications and improved outcomes. • Increased safety of this therapy and the use of alternative donors will enable its wider clinical use beyond the treatment of malignant diseases. • Although preventing GVHD while preserving GVT effects and improving immune reconstitution post-transplant are still the most challenging issues, recent advances have led to an improved understanding of GVHD and the suggestion of novel strategies to overcome these hurdles. HW. Li and M. Sykes. Nat Rev Immunol. 2012 May 25;12(6):403-16.
  73. 73. Thank you for your attention

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