Graft vs Tumor Effect
Graft vs Host Reaction
Graft vs Host Disease
Graft Survival
Transplantation, Homologous
Graft vs Leukemia Effect
Tumor Markers, Biological
Tumor Necrosis Factor-alpha
Tumor Burden
Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens. (1/164)
Allogeneic bone marrow transplantation (BMT) is a common treatment of hematologic malignancies. Recurrence of the underlying malignancy is a major cause of treatment failure. Donor-derived cytotoxic T lymphocytes (CTLs) specific for patients' minor histocompatibility antigens (mHags) play an important role in both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivities. mHags HA-1 and HA-2 induce HLA-A*0201-restricted CTLs in vivo and are exclusively expressed on hematopoietic cells, including leukemic cells and leukemic precursors, but not on fibroblasts, keratinocytes, or liver cells. The chemical nature of the mHags HA-1 and HA-2 is known. We investigated the feasibility of ex vivo generation of mHag HA-1- and HA-2-specific CTLs from unprimed mHag HA-1- and/or HA-2-negative healthy blood donors. HA-1 and HA-2 synthetic peptide-pulsed dendritic cells (DCs) were used as antigen-presenting cells (APC) to stimulate autologous unprimed CD8(+) T cells. The ex vivo-generated HA-1- and HA-2-specific CTLs efficiently lyse leukemic cells derived from acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) patients. No lytic reactivity was detected against nonhematopoietic cells. Sufficient numbers of the CTLs can be obtained for the adoptive immunotherapy purposes. In conclusion, we present a feasible, novel therapy for the treatment for relapsed leukemia after BMT with a low risk of GVHD. (+info)Rejection of an MHC class II negative tumor following induction of murine syngeneic graft-versus-host disease. (2/164)
Cyclosporin A (CsA) has been used clinically to induce graft-versus-host disease following autologous bone marrow transplantation in an attempt to destroy residual leukemia cells and reduce relapse. To analyze the antitumor potential of murine syngeneic graft-versus-host disease (SGVHD), C3H/HeN mice were lethally irradiated, reconstituted with T cell-depleted syngeneic bone marrow (ATBM) and treated with CsA for 21 days. Graft-versus-leukemia activity was assessed by challenging groups of olive oil-treated control ATBM (OO-ATBM) and CsA-treated (CsA-ATBM) mice 1 week after CsA therapy with graded doses of the syngeneic 38C13 B cell lymphoma. Following CsA treatment, up to 70% of CsA-ATBM developed SGVHD and more than 70% of the animals injected with 500 38C13 cells exhibited long-term survival (MST >80 days). In contrast, none of the OO-ATBM control mice developed SGVHD, and more than 75% of these mice died following injection of 500 38C13 tumor cells (MST = 34 days). Long-term survivors were not resistant to tumor challenge suggesting that tumor-specific immunity did not develop. Finally, class II negative 38C13 cells cultured in IL-4 or IL-10 were not inducible for MHC class II molecules, demonstrating that class II-independent antitumor mechanisms exist in SGVHD mice. (+info)Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. (3/164)
Allogeneic bone marrow transplantation (allo-BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect. In the present study, we examined the contribution of cytotoxic effector mechanisms, which are mediated by tumor necrosis factor-alpha (TNF-alpha), Fas ligand (FasL), or perforin, to GVHD and GVL effect in a murine BMT model. Bone marrow cells plus spleen cells (BMS) from wild-type, FasL-defective, or perforin-deficient donors were transferred into lethally irradiated recipients in the parent (C57BL/6) to F1 (C57BL/6 x DBA/2) BMT model with or without prior inoculation of DBA/2 leukemia L1210 or P815 mast cytoma cells. The effect of anti-TNF-alpha antibody administration was also examined. Whereas the defect or blockade of each cytotoxic pathway could ameliorate lethal acute GVHD, the GVL effect was differentially affected. The wild-type BMS recipients died of acute GVHD within 50 days without residual leukemia cells. The FasL-defective BMS recipients showed 60%< survival over 80 days without acute GVHD or residual leukemia cells. Administration of anti-TNF-alpha antibody resulted in early leukemia relapse and the recipients died within 25 days with massive leukemia infiltration in the liver. The perforin-deficient BMS recipients died within 60 days with residual leukemia cells. These results suggest that blockade of the Fas/FasL pathway could be used for ameliorating GVHD without impairing GVL effect in allo-BMT. (+info)Enhancement of graft-versus-tumor activity and graft-versus-host disease by pretransplant immunization of allogeneic bone marrow donors with a recipient-derived tumor cell vaccine. (4/164)
Allogeneic bone marrow transplantation (BMT) can be accompanied by a beneficial T cell-mediated antitumor immune response known as graft-versus-tumor (GVT) activity. However, BMT donor T cells are not exposed to target antigens of GVT activity until transfer to the host, where tumor antigen presentation may be suboptimal. This study tested in a murine model the hypothesis that immunization of MHC-matched allogeneic donors with a recipient-derived tumor cell vaccine would substantially increase GVT activity and extend survival of BMT recipients with preexisting micrometastatic tumor. C3H.SW and C57BL/10 mice were immunized against a C57BL/6-derived fibrosarcoma or leukemia, and they were used as BMT donors. Recipients were H-2-matched, minor histocompatibility antigen-mismatched C57BL/6 mice with previously established micrometastatic tumors. Donor immunization led to a significant increase in GVT activity that was T cell dependent and cell dose dependent. In some settings, donor immunization also prolonged survival of recipients with preexisting micrometastatic tumors. However, donor immunization significantly increased the incidence of fatal graft-versus-host disease such that long-term survival was uncommon. In vitro cytotoxicity assays indicated that donor immunization induced both tumor-selective and alloreactive cytolytic T-cell populations. In vivo cross-protection assays showed that a substantial portion of the GVT effect was mediated by alloreactive cells not specific for the immunizing tumor. In conclusion, immunization of allogeneic BMT donors with a recipient-derived whole tumor cell vaccine substantially increases GVT activity but also exacerbates graft-versus-host disease. (+info)Induction of a graft-versus-leukemia reaction by cyclosporin A withdrawal as immunotherapy for leukemia relapsing after allogeneic bone marrow transplantation. (5/164)
We studied the immunomodulating effect of withdrawal of immunosuppression with cyclosporin A (CsA) in 42 patients with leukemic relapse of chronic myelogenous leukemia (CML) (n = 24), acute myeloid leukemia (AML) (n = 13) and acute lymphoblastic leukemia (ALL) (n = 5) after allogeneic unmanipulated bone marrow (BMT) or peripheral blood stem cell transplantation (PBSCT). Response to CsA withdrawal was monitored molecularly by the polymerase chain reaction for elimination of CML cells containing the bcr-abl messenger RNA (mRNA) transcript (n = 24), or mll-af4 mRNA transcript characteristic of leukemic cells with a 11q23 chromosomal abnormality (n = 1). Rapid tapering of CsA resulted in subsequent achievement of cytogenetic remission in 11 of 14 CML patients (79%) who relapsed in early disease phase (n = 9 cytogenetic relapse, n = 2 hematological relapse) after a median of 57 days. Three of 13 AML patients and one of five ALL patients achieved complete remission. CsA withdrawal was accompanied by the development of acute graft-versus-host disease (GVHD) grade II in most of the 24 patients with CML. Two patients who achieved remission of AML or ALL died from severe GVHD grade III-IV. We calculated a probability of 84% for achieving and remaining in remission with early relapse of CML 4 years after relapse post BMT, whereas patients with AML have only a probability of about 10% of achieving and remaining in remission after 3 years. Patients with advanced CML and ALL had no chance of achieving and remaining in remission in the same time period. (+info)Relapse of chronic myeloid leukaemia 14 years after allogeneic bone marrow transplantation. (6/164)
Allogeneic bone marrow transplantation (BMT) is the treatment of choice for patients with chronic myeloid leukaemia (CML) who are relatively young and have suitable donors. Relapse is rare more than 5 years after allografting. We describe a patient who relapsed with myeloid blast transformation 14 years after allografting. This case suggests that leukaemia stem cells may on occasion remain quiescent for long periods and emphasises the importance of long-term follow-up after transplantation for CML. (+info)Opposing roles of CD28:B7 and CTLA-4:B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells. (7/164)
Blockade with B7 antagonists interferes with CD28:B7 and CTLA-4:B7 interactions, which may have opposing effects. We have examined the roles of CD28:B7 and CTLA-4:B7 on in vivo alloresponses. A critical role of B7:CD28 was demonstrated by markedly compromised expansion of CD28-deficient T cells and diminished graft-versus-host disease lethality of limited numbers of purified CD4+ or CD8+ T cells. When high numbers of T cells were infused, the requirement for CD28:B7 interaction was lessened. In lethally irradiated recipients, anti-CTLA-4 mAb enhanced in vivo donor T cell expansion, but did not affect, on a per cell basis, anti-host proliferative or CTL responses of donor T cells. Graft-versus-host lethality was accelerated by anti-CTLA-4 mAb infusion given early post-bone marrow transplantation (BMT), mostly in a CD28-dependent fashion. Donor T cells obtained from anti-CTLA-4 mAb-treated recipients were skewed toward a Th2 phenotype. Enhanced T cell expansion in mAb-treated recipients was strikingly advantageous in the graft-versus-leukemia effects of delayed donor lymphocyte infusion. In two different systems, anti-CTLA-4 mAb enhanced the rejection of allogeneic T cell-depleted marrow infused into sublethally irradiated recipients. We conclude that blockade of the selective CD28-B7 interactions early post-BMT, which preserve CTLA-4:B7 interactions, would be preferable to blocking both pathways. For later post-BMT, the selective blockade of CTLA-4:B7 interactions provides a potent and previously unidentified means for augmenting the GVL effect of delayed donor lymphocyte infusion. (+info)Granulocyte colony-stimulating factor-mobilized allogeneic stem cell transplantation maintains graft-versus-leukemia effects through a perforin-dependent pathway while preventing graft-versus-host disease. (8/164)
Minimization of graft-versus-host disease (GVHD) with preservation of the graft-versus-leukemia (GVL) effect is a crucial step to improve the overall survival of allogeneic bone marrow transplantation (BMT) for patients with hematological malignancies. We and other investigators have shown that granulocyte colony-stimulating factor (G-CSF)-mobilized allogeneic peripheral stem cell transplantation (PBSCT) reduces the severity of acute GVHD in murine models. In this study, we investigated whether G-CSF-mobilized PBSC maintain their GVL effect in a murine allogeneic transplant model (B6 --> B6D2F1). B6 mice (H-2(b)) were injected subcutaneously with human G-CSF (100 micrograms/kg/d) for 6 days and their splenocytes were harvested on day 7 as a source of PBSC. G-CSF mobilization dramatically improved transplant survival compared with nonmobilized controls (95% v 0%, P <.001). Systemic levels of lipopolysaccharide and tumor necrosis factor-alpha were markedly reduced in recipients of allogeneic G-CSF-mobilized donors, but cytolytic T lymphocyte (CTL) activity against host tumor target cells p815 was retained in those recipients. When leukemia was induced in recipients by coinjection of p815 tumor cells (H-2(d)) at the time of transplantation, all surviving recipients of G-CSF-mobilized B6 donors were leukemia-free at day 70 after transplant, whereas all mice who received T-cell-depleted (TCD) splenocytes from G-CSF-mobilized B6 donors died of leukemia. When splenocytes from G-CSF-mobilized perforin-deficient (pfp-/-) mice were used for transplantation, 90% of recipients died of leukemia, demonstrating that perforin is a crucial pathway mediating GVL effects after G-CSF-mobilized PBSCT. These data illustrate that G-CSF-mobilized allogeneic PBSCT separate GVL from GVHD by preserving perforin-dependent donor CTL activity while reducing systemic inflammation. (+info)The "Graft vs Tumor Effect" is a term used in the field of transplantation medicine, particularly in allogeneic hematopoietic stem cell transplantation (HSCT). It refers to the anti-tumor activity exhibited by donor immune cells (graft) against residual malignant cells (tumor) in the recipient's body.
After HSCT, the donor's immune system is reconstituted in the recipient's body. If the donor and recipient are not identical, there may be differences in their major and minor histocompatibility antigens, which can lead to a graft-versus-host disease (GVHD) where the donor's immune cells attack the recipient's tissues. However, these same donor immune cells can also recognize and target any residual tumor cells in the recipient's body, leading to a graft vs tumor effect.
This effect can contribute to the elimination of residual malignant cells and reduce the risk of relapse, particularly in hematological malignancies such as leukemia and lymphoma. However, it is important to balance this effect with the risk of GVHD, which can cause significant morbidity and mortality. Therefore, strategies such as donor selection, graft manipulation, and immunosuppressive therapy are used to optimize the graft vs tumor effect while minimizing GVHD.
A "Graft versus Host Reaction" (GVHR) is a condition that can occur after an organ or bone marrow transplant, where the immune cells in the graft (transplanted tissue) recognize and attack the recipient's (host's) tissues as foreign. This reaction occurs because the donor's immune cells (graft) are able to recognize the host's cells as different from their own due to differences in proteins called human leukocyte antigens (HLAs).
The GVHR can affect various organs, including the skin, liver, gastrointestinal tract, and lungs. Symptoms may include rash, diarrhea, jaundice, and respiratory distress. The severity of the reaction can vary widely, from mild to life-threatening.
To prevent or reduce the risk of GVHR, immunosuppressive drugs are often given to the recipient before and after transplantation to suppress their immune system and prevent it from attacking the graft. Despite these measures, GVHR can still occur in some cases, particularly when there is a significant mismatch between the donor and recipient HLAs.
Graft-versus-host disease (GVHD) is a condition that can occur after an allogeneic hematopoietic stem cell transplantation (HSCT), where the donated immune cells (graft) recognize the recipient's tissues (host) as foreign and attack them. This results in inflammation and damage to various organs, particularly the skin, gastrointestinal tract, and liver.
Acute GVHD typically occurs within 100 days of transplantation and is characterized by symptoms such as rash, diarrhea, and liver dysfunction. Chronic GVHD, on the other hand, can occur after 100 days or even years post-transplant and may present with a wider range of symptoms, including dry eyes and mouth, skin changes, lung involvement, and issues with mobility and flexibility in joints.
GVHD is a significant complication following allogeneic HSCT and can have a substantial impact on the patient's quality of life and overall prognosis. Preventative measures, such as immunosuppressive therapy, are often taken to reduce the risk of GVHD, but its management remains a challenge in transplant medicine.
Graft survival, in medical terms, refers to the success of a transplanted tissue or organ in continuing to function and integrate with the recipient's body over time. It is the opposite of graft rejection, which occurs when the recipient's immune system recognizes the transplanted tissue as foreign and attacks it, leading to its failure.
Graft survival depends on various factors, including the compatibility between the donor and recipient, the type and location of the graft, the use of immunosuppressive drugs to prevent rejection, and the overall health of the recipient. A successful graft survival implies that the transplanted tissue or organ has been accepted by the recipient's body and is functioning properly, providing the necessary physiological support for the recipient's survival and improved quality of life.
Homologous transplantation is a type of transplant surgery where organs or tissues are transferred between two genetically non-identical individuals of the same species. The term "homologous" refers to the similarity in structure and function of the donated organ or tissue to the recipient's own organ or tissue.
For example, a heart transplant from one human to another is an example of homologous transplantation because both organs are hearts and perform the same function. Similarly, a liver transplant, kidney transplant, lung transplant, and other types of organ transplants between individuals of the same species are also considered homologous transplantations.
Homologous transplantation is in contrast to heterologous or xenogeneic transplantation, where organs or tissues are transferred from one species to another, such as a pig heart transplanted into a human. Homologous transplantation is more commonly performed than heterologous transplantation due to the increased risk of rejection and other complications associated with xenogeneic transplants.
The "Graft versus Leukemia (GvL) Effect" is a term used in the field of hematopoietic stem cell transplantation to describe a desirable outcome where the donor's immune cells (graft) recognize and attack the recipient's leukemia cells (host). This effect occurs when the donor's T-lymphocytes, natural killer cells, and other immune cells become activated against the recipient's malignant cells.
The GvL effect is often observed in patients who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT), where the donor and recipient are not genetically identical. The genetic disparity between the donor and recipient creates an environment that allows for the recognition of host leukemia cells as foreign, triggering an immune response against them.
While the GvL effect can be beneficial in eliminating residual leukemia cells, it can also lead to complications such as graft-versus-host disease (GvHD), where the donor's immune cells attack the recipient's healthy tissues. Balancing the GvL effect and minimizing GvHD remains a significant challenge in allo-HSCT.
Graft occlusion in the context of vascular surgery refers to the complete or partial blockage of a blood vessel that has been surgically replaced or repaired with a graft. The graft can be made from either synthetic materials or autologous tissue (taken from another part of the patient's body).
Graft occlusion can occur due to various reasons, including:
1. Thrombosis: Formation of a blood clot within the graft, which can obstruct blood flow.
2. Intimal hyperplasia: Overgrowth of the inner lining (intima) of the graft or the adjacent native vessel, causing narrowing of the lumen and reducing blood flow.
3. Atherosclerosis: Deposition of cholesterol and other substances in the walls of the graft, leading to hardening and narrowing of the vessel.
4. Infection: Bacterial or fungal infection of the graft can cause inflammation, weakening, and ultimately occlusion of the graft.
5. Mechanical factors: Kinking, twisting, or compression of the graft can lead to obstruction of blood flow.
Graft occlusion is a significant complication following vascular surgery, as it can result in reduced perfusion to downstream tissues and organs, leading to ischemia (lack of oxygen supply) and potential tissue damage or loss.
Tumor markers are substances that can be found in the body and their presence can indicate the presence of certain types of cancer or other conditions. Biological tumor markers refer to those substances that are produced by cancer cells or by other cells in response to cancer or certain benign (non-cancerous) conditions. These markers can be found in various bodily fluids such as blood, urine, or tissue samples.
Examples of biological tumor markers include:
1. Proteins: Some tumor markers are proteins that are produced by cancer cells or by other cells in response to the presence of cancer. For example, prostate-specific antigen (PSA) is a protein produced by normal prostate cells and in higher amounts by prostate cancer cells.
2. Genetic material: Tumor markers can also include genetic material such as DNA, RNA, or microRNA that are shed by cancer cells into bodily fluids. For example, circulating tumor DNA (ctDNA) is genetic material from cancer cells that can be found in the bloodstream.
3. Metabolites: Tumor markers can also include metabolic products produced by cancer cells or by other cells in response to cancer. For example, lactate dehydrogenase (LDH) is an enzyme that is released into the bloodstream when cancer cells break down glucose for energy.
It's important to note that tumor markers are not specific to cancer and can be elevated in non-cancerous conditions as well. Therefore, they should not be used alone to diagnose cancer but rather as a tool in conjunction with other diagnostic tests and clinical evaluations.
Tumor Necrosis Factor-alpha (TNF-α) is a cytokine, a type of small signaling protein involved in immune response and inflammation. It is primarily produced by activated macrophages, although other cell types such as T-cells, natural killer cells, and mast cells can also produce it.
TNF-α plays a crucial role in the body's defense against infection and tissue injury by mediating inflammatory responses, activating immune cells, and inducing apoptosis (programmed cell death) in certain types of cells. It does this by binding to its receptors, TNFR1 and TNFR2, which are found on the surface of many cell types.
In addition to its role in the immune response, TNF-α has been implicated in the pathogenesis of several diseases, including autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, as well as cancer, where it can promote tumor growth and metastasis.
Therapeutic agents that target TNF-α, such as infliximab, adalimumab, and etanercept, have been developed to treat these conditions. However, these drugs can also increase the risk of infections and other side effects, so their use must be carefully monitored.
Tumor burden is a term used to describe the total amount of cancer in the body. It can refer to the number of tumors, the size of the tumors, or the amount of cancer cells in the body. In research and clinical trials, tumor burden is often measured to assess the effectiveness of treatments or to monitor disease progression. High tumor burden can cause various symptoms and complications, depending on the type and location of the cancer. It can also affect a person's prognosis and treatment options.
A cell line that is derived from tumor cells and has been adapted to grow in culture. These cell lines are often used in research to study the characteristics of cancer cells, including their growth patterns, genetic changes, and responses to various treatments. They can be established from many different types of tumors, such as carcinomas, sarcomas, and leukemias. Once established, these cell lines can be grown and maintained indefinitely in the laboratory, allowing researchers to conduct experiments and studies that would not be feasible using primary tumor cells. It is important to note that tumor cell lines may not always accurately represent the behavior of the original tumor, as they can undergo genetic changes during their time in culture.