Graft-versus-tumor effect

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Graft-versus-tumor effect (GvT) appears after allogeneic hematopoietic stem cell transplantation (HSCT). The graft contains donor T cells (T lymphocytes) that can be beneficial for the recipient by eliminating residual malignant cells. [1] GvT might develop after recognizing tumor-specific or recipient-specific alloantigens. It could lead to remission or immune control of hematologic malignancies. [2] This effect applies in myeloma and lymphoid leukemias, lymphoma, multiple myeloma and possibly breast cancer. [3] It is closely linked with graft-versus-host disease (GvHD), as the underlying principle of alloimmunity is the same. CD4+CD25+ regulatory T cells (Treg) can be used to suppress GvHD without loss of beneficial GvT effect. [4] The biology of GvT response is still not fully understood but it is probable that the reaction with polymorphic minor histocompatibility antigens expressed either specifically on hematopoietic cells or more widely on a number of tissue cells or tumor-associated antigens is involved. [5] [6] This response is mediated largely by cytotoxic T lymphocytes (CTL) but it can be employed by natural killers (NK cells) as separate effectors, particularly in T-cell-depleted HLA-haploidentical HSCT. [6]

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Graft-versus-leukemia

Graft-versus-leukemia (GvL) is a specific type of GvT effect. As the name of this effect indicates, GvL is a reaction against leukemic cells of the host. GvL requires genetic disparity because the effect is dependent on the alloimmunity principle. GvL is a part of the reaction of the graft against the host. Whereas graft-versus-host-disease (GvHD) has a negative impact on the host, GvL is beneficial for patients with hematopeietic malignancies. After HSC transplantation both GvL and GvHD develop. The interconnection of those two effects can be seen by comparison of leukemia relapse after HSC transplantation with development of GvHD. Patients who develop chronic or acute GvHD have lower chance of leukemia relapse. [7] When transplanting T-cell depleted stem cell transplant, GvHD can be partially prevented, but in the same time the GvL effect is also reduced, because T-cells play an important role in both of those effects. [8] The possibilities of GvL effect in the treatment of hematopoietic malignancies are limited by GvHD. The ability to induce GvL but not GvH after HSCT would be very beneficial for those patients. There are some strategies to suppress the GvHD after transplantation or to enhance GvL but none of them provide an ideal solution to this problem. For some forms of hematopoietic malignancies, for example acute myeloid leukemia (AML), the essential cells during HSCT are, beside the donor's T cells, the NK cells, which interact with KIR receptors. NK cells are within the first cells to repopulate host's bone marrow which means they play important role in the transplant engraftment. For their role in the GvL effect, their alloreactivity is required. [9] Because KIR and HLA genes are inherited independently, the ideal donor can have compatible HLA genes and KIR receptors that induce the alloreaction of NK cells at the same time. This will occur with most of the non-related donor. When transplanting HSC during AML, T-cells are usually selectively depleted to prevent GvHD while NK cells help with the GvL effect which prevent leukemia relapse. When using non-depleted T-cell transplant, cyclophosphamide is used after transplantation to prevent GvHD or transplant rejection. Other strategies currently clinically used for suppressing GvHD and enhancing GvL are for example optimization of transplant condition or donor lymphocyte infusion (DLI) after transplantation. [10] [11] However, none of those provide satisfactory universal results, thus other options are still being inspected. One of the possibilities is the use of cytokines. Granulocyte colony-stimulating factor (G-CSF) is used to mobilize HSC and mediate T cell tolerance during transplantation. G-CSF can help to enhance GvL effect and suppress GvHD by reducing levels of LPS and TNF-α. Using G-CSF also increases levels of Treg, which can also help with prevention of GvHD. Other cytokines can also be used to prevent or reduce GvHD without eliminating GvL, for example KGF, IL-11, IL-18 and IL-35. [11]

See also

Related Research Articles

Histocompatibility, or tissue compatibility, is the property of having the same, or sufficiently similar, alleles of a set of genes called human leukocyte antigens (HLA), or major histocompatibility complex (MHC). Each individual expresses many unique HLA proteins on the surface of their cells, which signal to the immune system whether a cell is part of the self or an invading organism. T cells recognize foreign HLA molecules and trigger an immune response to destroy the foreign cells. Histocompatibility testing is most relevant for topics related to whole organ, tissue, or stem cell transplants, where the similarity or difference between the donor's HLA alleles and the recipient's triggers the immune system to reject the transplant. The wide variety of potential HLA alleles lead to unique combinations in individuals and make matching difficult.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. They belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation. Most immune cells detect the antigen presented on major histocompatibility complex (MHC) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Anti-thymocyte globulin (ATG) is an infusion of horse or rabbit-derived antibodies against human T cells and their precursors (thymocytes), which is used in the prevention and treatment of acute rejection in organ transplantation and therapy of aplastic anemia due to bone marrow insufficiency.

<span class="mw-page-title-main">Hematopoietic stem cell transplantation</span> Medical procedure to replace blood or immune stem cells

Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce additional normal blood cells. It may be autologous, allogeneic or syngeneic.

<span class="mw-page-title-main">Graft-versus-host disease</span> Medical condition

Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.

<span class="mw-page-title-main">Hematopoietic stem cell</span> Stem cells that give rise to other blood cells

Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the (midgestational) aorta-gonad-mesonephros region, through a process known as endothelial-to-hematopoietic transition. In adults, haematopoiesis occurs in the red bone marrow, in the core of most bones. The red bone marrow is derived from the layer of the embryo called the mesoderm.

<span class="mw-page-title-main">Cell therapy</span> Therapy in which cellular material is injected into a patient

Cell therapy is a therapy in which viable cells are injected, grafted or implanted into a patient in order to effectuate a medicinal effect, for example, by transplanting T-cells capable of fighting cancer cells via cell-mediated immunity in the course of immunotherapy, or grafting stem cells to regenerate diseased tissues.

Transfusion-associated graft-versus-host disease (TA-GvHD) is a rare complication of blood transfusion, in which the immunologically competent donor T lymphocytes mount an immune response against the recipient's lymphoid tissue. These donor lymphocytes engraft, recognize recipient cells as foreign and mount an immune response against recipient tissues. Donor lymphocytes are usually identified as foreign and destroyed by the recipient's immune system. However, in situations where the recipient is severely immunocompromised, or when the donor and recipient HLA type is similar, the recipient's immune system is not able to destroy the donor lymphocytes. This can result in transfusion associated graft-versus-host disease. This is in contrast with organ/tissue transplant associated GvHD, where matching HLA reduces the incident of the complication.

<span class="mw-page-title-main">Minor histocompatibility antigen</span>

Minor histocompatibility antigen are peptides presented on the cellular surface of donated organs that are known to give an immunological response in some organ transplants. They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides. These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules's antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities' proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.

Juvenile myelomonocytic leukemia (JMML) is a rare form of chronic leukemia that affects children, commonly those aged four and younger. The name JMML now encompasses all diagnoses formerly referred to as juvenile chronic myeloid leukemia (JCML), chronic myelomonocytic leukemia of infancy, and infantile monosomy 7 syndrome. The average age of patients at diagnosis is two (2) years old. The World Health Organization has included JMML as a subcategory of myelodysplastic and myeloproliferative disorders.

Donor lymphocyte infusion (DLI) or buffy coat infusion is a form of adoptive immunotherapy used after hematopoietic stem cell transplantation.

<span class="mw-page-title-main">CD226</span> Protein-coding gene in the species Homo sapiens

CD226, PTA1 or DNAM-1 is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.

A humanized mouse is a mouse carrying functioning human genes, cells, tissues, and/or organs. Humanized mice are commonly used as small animal models in biological and medical research for human therapeutics.

TK is an experimental cell therapy which may be used to treat high-risk leukemia. It is currently undergoing a Phase III clinical trial to determine efficacy and clinical usefulness.

<span class="mw-page-title-main">Haematopoietic system</span>

The haematopoietic system is the system in the body involved in the creation of the cells of blood.

Microtransplantation (MST) is an advanced technology to treat malignant hematological diseases and tumors by infusing patients with granulocyte colony-stimulating factor (G-CSF) mobilized human leukocyte antigen (HLA)-mismatched allogeneic peripheral blood stem cells following a reduced-intensity chemotherapy or targeted therapy. The term "microtransplantation" comes from its mechanism of reaching donor cell microchimerism.

Guo Mei is a hematologist and associate director of 307th Hospital of Chinese People’s Liberation Army and deputy director of Radiation Research Institute.

T-cell depletion (TCD) is the process of T cell removal or reduction, which alters the immune system and its responses. Depletion can occur naturally or be induced for treatment purposes. TCD can reduce the risk of graft-versus-host disease (GVHD), which is a common issue in transplants. The idea that TCD of the allograft can eliminate GVHD was first introduced in 1958. In humans the first TCD was performed in severe combined immunodeficiency patients.

In the immune system, veto cells are white blood cells that have a selective immunomodulation properties. Veto cells were first described in 1979 as cells that “can prevent generation of cytotoxic lymphocytes by normal spleen cells against self-antigens”. Hence, veto cells delete T cells that recognize the veto cells.

<span class="mw-page-title-main">Shimon Slavin</span> Israeli professor of medicine

Shimon Slavin is an Israeli professor of medicine. Slavin pioneered the use of immunotherapy mediated by allogeneic donor lymphocytes and innovative methods for stem cell transplantation for the cure of hematological malignancies and solid tumors, and using hematopoietic stem cells for induction of transplantation tolerance to bone marrow and donor allografts.

References

  1. ↑ Thompson LF, Tsukamoto H, Chernogorova P, Zeiser R (January 2013). "A delicate balance: CD73-generated adenosine limits the severity of graft vs. host disease but also constrains the allogeneic graft vs. tumor effect". Oncoimmunology. 2 (1): e22107. doi:10.4161/onci.22107. PMC   3583907 . PMID   23482243.
  2. ↑ Kolb HJ (December 2008). "Graft-versus-leukemia effects of transplantation and donor lymphocytes". Blood. 112 (12): 4371–83. doi: 10.1182/blood-2008-03-077974 . PMID   19029455.
  3. ↑ Childs RW, Clave E, Tisdale J, Plante M, Hensel N, Barrett J (July 1999). "Successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitor-cell transplant: evidence for a graft-versus-tumor effect". Journal of Clinical Oncology. 17 (7): 2044–9. doi:10.1200/jco.1999.17.7.2044. PMID   10561256.
  4. ↑ Vagianos C, Polydorou A, Karatzas T, Vagenas C, Stavropoulos M, Androulakis J (1992). "Successful treatment of postoperative external biliary fistula by selective nasobiliary drainage". HPB Surgery. 6 (2): 115–20, discussion 120–4. doi: 10.1155/1992/58436 . PMC   2443016 . PMID   1292584.
  5. ↑ Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R, et al. (March 2005). "Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning". Journal of Clinical Oncology. 23 (9): 1993–2003. doi: 10.1200/JCO.2005.08.136 . hdl:2268/102049. PMID   15774790.
  6. 1 2 Rezvani AR, Storb RF (May 2008). "Separation of graft-vs.-tumor effects from graft-vs.-host disease in allogeneic hematopoietic cell transplantation". Journal of Autoimmunity. 30 (3): 172–9. doi:10.1016/j.jaut.2007.12.002. PMC   2329571 . PMID   18242060.
  7. ↑ Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. (February 1990). "Graft-versus-leukemia reactions after bone marrow transplantation". Blood. 75 (3): 555–62. doi: 10.1182/blood.V75.3.555.555 . PMID   2297567.
  8. ↑ Kolb HJ, Schmid C, Barrett AJ, Schendel DJ (February 2004). "Graft-versus-leukemia reactions in allogeneic chimeras". Blood. 103 (3): 767–76. doi: 10.1182/blood-2003-02-0342 . PMID   12958064.
  9. ↑ Falco M, Pende D, Munari E, Vacca P, Mingari MC, Moretta L (April 2019). "Natural killer cells: From surface receptors to the cure of high-risk leukemia (Ceppellini Lecture)". HLA. 93 (4): 185–194. doi:10.1111/tan.13509. PMC   6767140 . PMID   30828978.
  10. ↑ Warren EH, Deeg HJ (April 2013). "Dissecting graft-versus-leukemia from graft-versus-host-disease using novel strategies". Tissue Antigens. 81 (4): 183–93. doi:10.1111/tan.12090. PMC   3645301 . PMID   23510414.
  11. 1 2 Chang YJ, Zhao XY, Huang XJ (2018-12-21). "Strategies for Enhancing and Preserving Anti-leukemia Effects Without Aggravating Graft-Versus-Host Disease". Frontiers in Immunology. 9: 3041. doi: 10.3389/fimmu.2018.03041 . PMC   6308132 . PMID   30619371.
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