Expression Of Histocompatibility Antigens Research Articles

Knockdown of swine leukocyte antigen expression in porcine lung transplants enables graft survival without immunosuppression.

Immune rejection remains the major obstacle to long-term survival of allogeneic lung transplants. The expression of major histocompatibility complex molecules and minor histocompatibility antigens triggers allogeneic immune responses that can lead to allograft rejection. Transplant outcomes therefore depend on long-term immunosuppression, which is associated with severe side effects. To address this problem, we investigated the effect of genetically engineered transplants with permanently down-regulated swine leukocyte antigen (SLA) expression to prevent rejection in a porcine allogeneic lung transplantation (LTx) model. Minipig donor lungs with unmodified SLA expression (control group, n = 7) or with modified SLA expression (treatment group, n = 7) were used to evaluate the effects of SLA knockdown on allograft survival and on the nature and strength of immune responses after terminating an initial 4-week period of immunosuppression after LTx. Genetic engineering to down-regulate SLA expression was achieved during ex vivo lung perfusion by lentiviral transduction of short hairpin RNAs targeting mRNAs encoding β2-microglobulin and class II transactivator. Whereas all grafts in the control group were rejected within 3 months, five of seven animals in the treatment group maintained graft survival without immunosuppression during the 2-year monitoring period. Compared with controls, SLA-silenced lung recipients had lower donor-specific antibodies and proinflammatory cytokine concentrations in the serum. Together, these data demonstrate a survival benefit of SLA-down-regulated lung transplants in the absence of immunosuppression.

LMP7 polymorphism may modify the presentation and clinical impact of minor histocompatibility antigens in matched related hematopoietic stem cell transplantation

Differential expression of minor histocompatibility antigens between the recipient and donor determines their disparity and can be modified by immunoproteasomes that regulate their processing and presentation. We examined the impact of HA-1 and HA-8 disparity, and immunoproteasome LMP7 polymorphism in 130 pairs. In multivariate analysis, HA-1 disparity showed a statistically significant association with an increased incidence of acute graft-versus-host disease (aGVHD) II–IV (p = 0.043, HR: 3.71, 95%CI = 1.04–13.26), while LMP7-Q/Q showed a trend toward increased incidence of aGVHD compared to LMP7-Q/K and K/K genotypes (p = 0.087, HR: 2.36, 95%CI = 0.88–6.31). All HA-1 and HA-8 disparate patients who developed aGVHD had the LMP7-Q/Q genotype. No significant association could be detected between HA-1, HA-8, or LMP7 and chronic GVHD, relapse-free survival (RFS), overall survival (OS), or transplant-related mortality (TRM). In conclusion, we suggested an association between the HA-1 disparity and the risk of developing aGVHD with a possible modifying effect of LMP7.

Possible association between benign migratory glossitis and fissured tongue with psoriasis: A meta-analysis

Psoriasis is a chronic inflammatory dermatological disease that affects approximately 2% of the population. It is related to geographic tongue (GT) because both present similar clinical, histopathological, and genetic patterns, suggesting that GT could represent an oral manifestation of psoriasis. The objective of this study is to assess the possible relationship between psoriasis and its possible oral manifestations such as GT and/or fissured tongue (FT). A search for the articles on psoriasis and tongue or oral mucosa was performed in the next electronic databases: PubMed (MEDLINE and Cochrane Library), Web of Science, and Spanish Medical Index (SMI). From 175 potentially eligible articles, 151 were excluded for the several reasons: articles without full-text availability (119) and studies without clinical or usable data (32). Finally, 24 studies were included in this meta-analysis. The data were analyzed using the statistical software RevMan 5.4 (The Cochrane Collaboration, Oxford, UK). For dichotomous outcomes, the estimates of effects of an intervention were expressed as odds ratios (OR) with 95% confidence intervals. Among patients with psoriasis, 8.6% had a GT and 28.2% had a FT. Psoriasis patients were more likely to present both GT (OR: 3.61, P < 0.001) or FT (OR: 2.84, P < 0.001). Regarding the expression of histocompatibility antigens, patients with psoriasis and GT more frequently expressed type B13 and B57 antigens, whereas controls without psoriasis or GT showed more types B15, B17, B40, B58, C04, Cw6, DR5, and DRw6 antigens. Geographical tongue and FT are most often observed in patients with psoriasis.

CAR T cells generated in situ using gene therapy in naturally activated lymph node T cells

Abstract T cells expressing chimeric antigen receptors (CAR T cells) are manufactured outside the body using non-physiological activation and in vitro culture protocols. The procedure takes 3 weeks and costs approximately $450,000 to administer. We have devised a scheme using mouse models for manufacturing CAR T cells in just 3 days employing a natural, polyclonal anti-viral immune response inside a lymph node (LN) using off the shelf reagents that can be applied widely in populations. CAR T cells emerge from the LN within a week, invade solid tumor, and eliminate the targeted antigen-positive tumor cells. Polyclonal activation of T cells is achieved by modifying the antigen presenting properties of lymph node resident professional antigen presenting cells (APC) through viral expression of allogeneic major histocompatibility antigens. The ensuing polyclonal activation occurs in the context of virus activated APC within the normal aarchitecture of the LN and confers robust T cell activation signals directing the development of cytolytic T cells. During the course of T cell activation, the T cells are transduced in situ with retroviruses encoding selected CARs. This approach could be applied to any number of different CARs to target a variety of tumors. T cells activated in the lymph node are functionally distinct from those activated using standard CAR T manufacturing protocols. We anticipate that CAR T cells generated in situ to natural stimuli will exhibit more normal immune regulatory properties that will impact their therapeutic utility. Because our approach uses off the shelf reagents and is administered using standard clinical procedures, cost to patients should be lowered and access to therapy increased.

Interactions between the immune system and the ruminant conceptus

Interactions of the conceptus with the immune system can involve either anti-sperm or anti-conceptus immune responses that limit the success of pregnancy of beneficial effects of cytokines released from lymphoid cells on embryonic growth and gene expression. The immune system is functional in the uterus and therefore there is the potential for anti-conceptus immune responses. However, endometrial lymphocytes are distinct in many respects from lymphoid cells at peripheral sites; one major subpopulation expresses the gamma delta T-cell receptor and may not recognize major histocompatibility antigens. There are also several control systems to limit anti-conceptus immune responses. In particular, expression of major histocompatibility antigens on the trophoblast is either absent or of limited distribution. In addition, activation of anti-conceptus immune responses leading to cytolytic responses is further limited by the presence of molecules that can inhibit lymphocyte transformation. The most well-characterized of these are prostaglandin E2 from placental and endometrial tissues, interferon-tau from the trophoblast during early pregnancy, and two endometrial proteins called the uterine milk proteins (UTMP). Progesterone plays a central role in inhibition of immune responses in actions that are mediated at least in part through endometrial secretion of UTMP. Cytokines play important roles as autocrine and paracrine regulators in many tissues including the reproductive tract. In ruminants, the best described example is interferon-tau. Other cytokines found in the reproductive tract or produced by the conceptus include interleukin-1, leukaemia inhibitory factor, granulocyte-macrophage colony stimulating factor and interleukin-6. It is possible that the major source of cytokines in the reproductive tract is non-lymphoid cells of the endometrium and trophoblast. It is not known to what extent endometrial lymphocytes contribute to the cytokine milieu because no cytokine has been identified as a product of endometrial lymphocytes. However, there is a population of granulated lymphocytes that increase in number and granularity in the luminal epithelium of the late-pregnant ewe that is a potential source of cytokines.

Experience with intravenous immunoglobulin treatment in pregnant women with miscarriage and chronic endometritis

Chronic endometritis is the most common endometrial pathology in women with habitual miscarriage. Urogenital infections, persistence of pathogenic and opportunistic flora lead to chronic inflammatory process in the endometrium and secondary immunodeficiency states. In the endometrium, an increased number of NK- (CD16+ and CD56+), В- (CD20+) lymphocytes and cells expressing the late HLA-DR activation marker are determined. These lymphocytes enhance the expression of histocompatibility antigens by endometrial cells and lead to autoimmune inflammation. The imbalance between immune tolerance to the fetus and immune activation to the pathogenic organisms is associated with poor pregnancy outcomes. After a course of complex therapy of chronic endometritis, most women with miscarriage can only reduce the severity of the inflammatory process in the endometrium. The aim of this study was to assess the importance of immunomodulatory effects of human immunoglobulin during pregnancy in women with miscarriage. The study included 182 patients with a history of miscarriage and chronic endometritis. Group 1 consisted of 98 women who received an intravenous course of human immunoglobulin at 7/8 weeks of pregnancy. Group 2 comprised 84 pregnant women who did not receive immunoglobulin therapy. An analysis of the results of the course and outcomes of pregnancy showed that administering an intravenous immunoglobulin course to pregnant women with miscarriage and chronic endometritis in the history prior to the first wave of trophoblast invasion helps to reduce the frequency of threatened abortion (54% in group 1 and 95% in group 2, p &lt; 0.001). The data obtained suggest that intravenous immunoglobulin should be recommended for women with habitual miscarriage and chronic endometritis during pregnancy up to 8 weeks.

Effect of Dexamethasone, LPS, or INFγ on the production of TNFα, IL-12, IL-6, IL-10, CXCL8, CXCL10, and CLC3, by bovine macrophages infected in vitro with Mycobacterium avium paratuberculosis.

Effect of Dexamethasone, LPS, or INFγ on the production of TNFα, IL-12, IL-6, IL-10, CXCL8, CXCL10, and CLC3, by bovine macrophages infected in vitro with Mycobacterium avium paratuberculosis.

Exploit of easy handling model mice with hypertension

Antigen expression by fetal cells near the mother is of interest because of the possibility that some antigens may stimulate beneficial maternal immune responses or may prevent the development of harmful responses. The recent generation of monoclonal antibodies to amnion and trophoblast antigens together with the finding that class I histocompatibility antigen (HLA) expression by amnion cells can be manipulated provided an opportunity to determine if any relationships exist among expression of HLA, amnion antigens, and trophoblast antigens. The results of the present study demonstrate that: (1) class I HLA and amnion-specific antigens are co-expressed by IFN-γ-modulated amnion cells, so neither prevents expression of the other; (2) EGF enhances expression of two amnion-specific antigens; (3) amnion cells do not express transferrin receptors, placental alkaline phosphatase, or other antigens normally associated with trophoblasts following exposure to IFN-γ and/or EGF. The results demonstrate independent modulation of expression of class I HLA, two amnion-specific antigens, and some trophoblast-associated antigens on amnion epithelial cells.

Intracellular bacteria in placental basal plate localize to extravillous trophoblasts

We previously showed that intracellular bacteria are present in the human placental maternal–fetal interface (basal plate). To determine the bacterial niche, basal plate biopsies were 1) examined histologically, and 2) cultured ex vivo, infected with either gram negative (Escherichia coli) or positive (Listeria monocytogenes) bacteria, and examined by histological staining, immunofluorescence, and transmission electron microscopy. We found bacteria in fetal extravillous trophoblasts (EVTs) in basal plate biopsies. Both E. coli and L. monocytogenes also predominantly invaded EVTs in basal plate explants where they replicated and formed clusters or existed as single organisms. EVTs are the cell type most susceptible to bacterial colonization, likely due to their expression of major histocompatibility antigen and immune-privileged status. Pathogens persisting and replicating in the EVTs may constitute a source of intrauterine colonization that leads to adverse outcomes such as preterm birth.

Systemic minor histocompatibility antigen expression in blood endothelial cells prevents T cell‐mediated vascular immunopathology

Attenuation of T cell-mediated damage of blood endothelial cells (BECs) in transplanted organs is important to prevent transplant vasculopathy (TV) and chronic rejection. Here, we assessed the importance of minor histocompatibility antigen (mHA) distribution and different coinhibitory molecules for T cell-BEC interaction. A transgenic mHA was directed specifically to BECs using the Tie2 promoter and cellular interactions were assessed in graft-versus-host disease-like and heterotopic heart transplantation settings. We found that cognate CD4(+) T-cell help was critical for the activation of BEC-specific CD8(+) T cells. However, systemic mHA expression on BECs efficiently attenuated adoptively transferred, BEC-specific CD4(+) and CD8(+) T cells and hence prevented tissue damage, whereas restriction of mHA expression to heart BECs precipitated the development of TV. Importantly, the lack of the coinhibitory molecules programmed death-1 (PD-1) and B and T lymphocyte attenuator fostered the initial activation of BEC-specific CD4(+) T cells, but did not affect development of TV. In contrast, TV was significantly augmented in the absence of PD-1 on BEC-specific CD8(+) T cells. Taken together, these results indicate that antigen distribution in the vascular bed determines the impact of coinhibition and, as a consequence, critically impinges on T cell-mediated vascular immunopathology.

Foot-and-mouth disease virus 3C protease induces fragmentation of the Golgi compartment and blocks intra-Golgi transport.

Picornavirus infection can cause Golgi fragmentation and impose a block in the secretory pathway which reduces expression of major histocompatibility antigens at the plasma membrane and slows secretion of proinflammatory cytokines. In this study, we show that Golgi fragmentation and a block in secretion are induced by expression of foot-and-mouth disease virus (FMDV) 3Cpro and that this requires the protease activity of 3Cpro. 3Cpro caused fragmentation of early, medial, and late Golgi compartments, but the most marked effect was on early Golgi compartments, indicated by redistribution of ERGIC53 and membrin. Golgi fragments were dispersed in the cytoplasm and were able to receive a model membrane protein exported from the endoplasmic reticulum (ER). Golgi fragments were, however, unable to transfer the protein to the plasma membrane, indicating a block in intra-Golgi transport. Golgi fragmentation was coincident with a loss of microtubule organization resulting from an inhibition of microtubule regrowth from the centrosome. Inhibition of microtubule regrowth also required 3Cpro protease activity. The loss of microtubule organization induced by 3Cpro caused Golgi fragmentation, but loss of microtubule organization does not block intra-Golgi transport. It is likely that the block of intra-Golgi transport is imposed by separate actions of 3Cpro, possibly through degradation of proteins required for intra-Golgi transport.

Epigenetic therapies: novel strategies for improving outcomes in myeloid malignancies

In haematological malignancies acquired abnormalities in chromatin structure are increasingly recognised as an important mechanism of leukemogenesis. Hypermethylation of promoter CpG islands results in the down-regulation of a range of tumor suppressor and pro-apoptotic genes which is plausibly linked with the acquisition of a neoplastic phenotype. Similarly, acquired changes in the acetylation and methylation status of histones caused by distinct leukemia fusion proteins result in transcriptional deregulation which contributes to the disease phenotype in patients with Acute Myeloid Leukaemia (AML) and myelodysplasia (MDS). It is therefore of great interest that pharmacological agents such as DNA methyltransferase inhibitors (DNMTI) and histone deacetylase inhibitors (HDI) with the capacity to reverse acquired chromatin abnormalities demonstrate significant clinical activity in patients with high risk MDS and AML. Indeed the activity of DNMTIs such as 5-azacitidine (AZA), when administered alone or in combination with an HDI, has led to their emergence as one of the most important recent therapeutic advances in the management of MDS and AML in the last two decades. It remains the case however that the molecular mechanism by which this new class of agents exerts an anti-tumor effect remains unknown. Critically the extent to which their clinical activity is dependent on re-induction of epigenetically silenced tumour suppressor or pro-apoptotic genes or whether their anti-tumor effect is mediated through an alternative mechanism remains unknown. It is now clear that the acquired abnormalities in chromatin structure which characterise many malignancies also result in reduced expression of a number of candidate tumor antigens, including members of the cancer testis antigen family such as MAGE-A1 and MAGE-A3. Importantly there is convincing evidence, in solid tumors and haematological malignancies, that DNMTIs such as AZA and 5-aza-2’-deoxycytidine (decitabine) up-regulate the expression of epigenetically repressed putative tumor antigens thereby potentially increasing tumor immunogenicity. Furthermore AZA also increases the expression of HLA Class 1 and co-stimulatory molecules such asCD80 and CD86 on the surface of leukemic blasts. The observation that demethylating agents may modulate a tumor-specific immune response also suggest that epigenetic therapies might be used to enhance the clinical activity of both autologous and allogeneic immunotherapeutic strategies. Studies from have previously demonstrated that up-regulation of the minor histocompatibility antigen HA-1 on solid tumors by decitabine sensitises tumor cells to recognition by HA-1 specific cytotoxic T lymphocytes and there is a now compelling case to investigate further the role of epigenetic agents as a priming agent in settings such as peptide vaccination. Epigenetic therapies also hold promise as a potential mechanism of selectively augmenting an immunologically mediated graft-versus-leukaemia (GVL) effect after allogeneic stem cell transplantation. In principle the ability of DNMTI to up-regulate the expression of epigenetically silenced tumor antigens without concomitantly increasing the expression of minor histocompatibility antigens on skin, gut or liver offers the possibility of increasing a GVL effect without a concomitant risk of GVHD. In this context the recent demonstration that post-transplant AZA, albeit at lower doses, is well-tolerated and induces a CD8+ T cell response to candidate tumor antigens post-transplant is of great interest and supports the further examination of AZA as post-transplant therapy.

Minor histocompatibility antigens and the maternal immune response to the fetus during pregnancy.

The tolerance of the semiallogeneic fetus by the maternal immune system is an important area of research for understanding how the maternal and fetal systems interact during pregnancy to ensure a successful outcome. Several lines of research reveal that the maternal immune system can recognize and respond to fetal minor histocompatibility antigens during pregnancy. Reactions to these antigens arise because of allelic differences between the mother and fetus and have been shown more broadly to play an important role in mediating transplantation outcomes. This review outlines the discovery of minor histocompatibility antigens and their importance in solid organ and hematopoietic stem cell transplantations, maternal T-cell responses to minor histocompatibility antigens during pregnancy, expression of minor histocompatibility antigens in the human placenta, and the potential involvement of minor histocompatibility antigens in the development and manifestation of pregnancy complications.

Impact of the hypomethylating agent 5-azacytidine on dendritic cells function

Recent evidence suggested that 5-azacytidine (5-aza) can impact important immune functions via epigenetic modifications, making it an attractive candidate for pharmacologic manipulation of the immune system. The aim of this work was to study the effects of 5-aza on human dendritic cells (DC) generated from peripheral blood monocytes, and to test the type of immune response induced in patients treated with 5-aza. On the phenotypic level, CD40 and CD86 expression was significantly increased on mature DC exposed to 5-aza (5-aza-DC), compared with control untreated DC. Mature control DC and mature 5-aza-DC secreted comparable amounts of interleukin (IL)-6, IL-12p70, IL-23, and tumor necrosis factor-α. However, mature 5-aza-DC secreted significantly lower levels of IL-10 and IL-27 compared to mature control DC (p = 0.04 and p = 0.005, respectively). In the peripheral blood of 14 patients (7 males and 7 females; age range, 53-81 years) with advanced myeloid malignancies (8 acute myeloid leukemia and 6 myelodysplastic syndrome) treated with 5-aza, there was a significant decrease of IL-4-secreting CD4(+) T cells (p = 0.001), and a significant increase of IL-17A- and IL-21-secreting CD4(+) T cells (p = 0.003 and p = 0.01, respectively, compared to 5 healthy donors) suggesting a Th17 response pattern in the blood of patients receiving 5-aza. In all, these data suggest potentially novel mechanisms of action of epigenetic therapies, such as 5-aza, which may have broader implications for immunotherapeutic strategies.

How to choose the best available homograft to reconstruct the right ventricular outflow tract

How to choose the best available homograft to reconstruct the right ventricular outflow tract

5-Azacytidine as Salvage Treatment in Relapsed Myeloid Tumors after Allogeneic Bone Marrow Transplantation

Relapse after allogeneic blood or marrow transplantation carries a very poor prognosis. Current strategies for management that include donor lymphocyte infusions (DLIs) and salvage chemotherapies are usually toxic and ineffective. Here we report the outcome of 10 patients with myeloid malignancies that received 5-azacytidine after a failed allogeneic bone marrow transplant. Of the 10 patients, 6 achieved a complete remission, 1 had stable disease, and 3 progressed after a median of 6 cycles administered. Only 1 patient has died (of disease progression), and no flares of graft-versus-host disease (GVHD) were observed with 5-azacytidine. As of latest follow-up, the median overall survival (OS) for the group was 422.5 days (127-1411). These results further suggest that 5-azacytidine is an active agent after failing an allogeneic bone marrow transplant, and prospective studies are warranted.

Major histocompatibility complex (MHC)-mediated immune regulation of decidual leukocytes at the fetal–maternal interface

Self and non-self recognition is the key mechanism by which the immune system determines whether or not to mount an immune response. During pregnancy the maternal immune system must tolerate the persistence of non-self semi-allogeneic fetal cells in the maternal tissue. Although many mechanisms have been shown to contribute to the prevention of a destructive maternal immune response to fetal cells, the immune acceptance of the allogeneic fetus in pregnancy largely remains an immunological paradox (Billingham et al., 1953). The aim of this review is to describe the expression of the polymorphic histocompatibility antigens at the fetal-maternal interface, their interaction with maternal leukocytes and their possible roles in immune regulation at the fetal-maternal interface during human pregnancy.

A Review of Studies on Targeting Interleukin 4 Receptor for Central Nervous System Malignancy

Despite advances in biomedical sciences, the prognosis of patients with brain tumors remains poor. Effective treatment is lacking for these central nervous system (CNS) cancers. Targeted immunotoxins are a new class of therapeutic approaches that have emerged for the treatment of human cancers. In this approach, tumor antigen or cell surface receptor is targeted by a chimeric fusion protein consisting of an antibody or a ligand and a suicidal gene or toxin to kill tumor cells. In that regard, receptors for interleukin (IL)-4 (IL-4R) have been identified to be overexpressed on a variety of human CNS tumor cell lines and tissue samples including meningioma. In various studies, high grade brain tumor specimens and malignant brain tumor cell lines have been shown to overexpress high-affinity IL-4R, while normal brain samples or cell lines expressed lower levels of these receptors. The structures of IL-4R on CNS tumors have been studied, which demonstrate that these cells express predominantly type II IL-4R. These receptors are functional as IL-4 can cause signal transduction, inhibit growth of some tumor cell lines and increase expression of major histocompatibility antigens and intracellular adhesion molecular-1 (ICAM-1) on some tumor cells lines. To target IL-4R, a chimeric fusion protein composed of IL-4 and truncated Pseudomonas exotoxin has been developed. This cytotoxin is highly cytotoxic to IL-4R positive tumors in vitro and has been reported to be highly effective in pre-clinical animal model of human brain cancer. Several Phase I/II clinical trials for treatment of IL-4R positive cancers have been completed. This review article will summarize pre-clinical and clinical development of IL-4PE cytotoxin.

Growth and major histocompatibility antigen expression regulation by IL-4, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) on human renal cell carcinoma.

We have recently shown that human renal cell carcinoma (RCC) tumour lines express high-affinity IL-4 receptors. Binding of IL-4 to RCC cells induced a growth inhibition in the range of 20-68%. To enhance the growth inhibitory effect of IL-4, we have tested the effects of two additional cytokines capable of directly affecting tumour cell growth. IFN-gamma caused a significant inhibition of RCC tumour cell growth (up to 70%) in a dose-dependent manner, whereas the effect of TNF-alpha was more limited (0-20% inhibition). The addition of IL-4 to IFN-gamma on RCC cells sensitive to IL-4 induced a greater inhibition of cell growth than that seen with each cytokine alone. IL-4 and IFN-gamma rendered RCC cells more responsive to the inhibitory effect mediated by TNF-alpha. The combination of TNF-alpha with IL-4 and IFN-gamma induced an optimal growth inhibition (up to 90-98%) of RCC cells. In addition to a direct anti-proliferative effect, we have demonstrated that these cytokines can also enhance the expression of MHC antigens on the surface of RCC tumour cell lines which may render the cells more immunogenic. All RCC lines tested expressed class I antigens, but not class II antigens. IFN-gamma induced class II expression and up-regulated the expression of class I antigens on RCC cells. Class II antigen expression was detectable following 48 h incubation, and greater after 72 h with IFN-gamma. IL-4 minimally affected class I expression, whereas TNF-alpha up-regulated class I antigen expression. IL-4 or TNF-alpha did not induce class II expression. The combination of the three cytokines slightly augmented the up-regulation of class I and class II antigens observed with IFN-gamma alone. These observations confirm the direct interaction of IL-4, IFN-gamma and TNF-alpha with RCC tumour cells, both at the level of growth regulation and MHC antigen expression, and suggest a therapeutic potential of the combination of the three cytokines for renal cell carcinoma.

Aberrant expression of BCL2A1-restricted minor histocompatibility antigens in melanoma cells: application for allogeneic transplantation

It has been shown that allogeneic hematopoietic stem cell transplantation (HSCT) can be one of the therapeutic options for patients with metastatic solid tumors, such as renal cancer. However, the development of relatively severe GVHD seems to be necessary to achieve tumor regression in the current setting. Thus, it is crucial to identify minor histocompatibility antigens (mHags) only expressed in tumor cells but not GVHD target organs. In this study, we examined whether three mHags: ACC-1 and ACC-2 encoded by BCL2A1, and HA-1 encoded by HMHA1, could serve as such targets for melanoma. Real-time PCR and immunohistochemical analysis revealed that the expression of both BCL2A1and HMHA1 in melanoma cell lines and primary melanoma cells was comparable to that of hematopoietic cells. Indeed, melanoma cell lines were efficiently lysed by cytotoxic T lymphocytes specific for ACC-1, ACC-2, and HA-1. Our data suggest that targeting mHags encoded not only by HMHA1, whose aberrant expression in solid tumors has been reported, but also BCL2A1 may bring about beneficial selective graft-versus-tumor effects in a population of melanoma patients for whom these mHags are applicable.