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Specific odors can induce memories of the past, especially those associated with autobiographical and episodic memory. Odors associated with autobiographical memories have been found to elicit stronger activation in the orbitofrontal cortex, hippocampus, and parahippocampus compared with odors not linked to personal memories. Here, we examined whether continuous odor stimuli associated with autobiographical memories could activate the above olfactory areas in older adults and speculated regarding whether this odor stimulation could have a protective effect against age-related cognitive decline. Specifically, we used functional magnetic resonance imaging to investigate the relationship between blood oxygen levels in olfactory regions and odor-induced subjective memory retrieval and emotions associated with autobiographical memory in older adults. In our group of healthy older adults, the tested odors induced autobiographical memories that were accompanied by increasing levels of retrieval and the feeling of being “brought back in time.” The strength of the subjective feelings, including vividness of the memory and degree of comfort, impacted activation of the left fusiform gyrus and left posterior orbitofrontal cortex. Further, our path model suggested that the strength of memory retrieval and of the emotions induced by odor-evoked autobiographical memories directly influenced neural changes in the left fusiform gyrus, and impacted left posterior orbitofrontal cortex activation through the left fusiform response.

Introduction Pathological abnormalities first appear in the medial temporal regions including entorhinal cortex and parahippocampus in patients with Alzheimer's disease. Previous studies showed that olfactory decline in elderly subjects was associated with volume reductions in the left hippocampus and left parahippocampus without cognitive impairment. The aim of this study is to investigate the link between olfaction and volume reductions in the medial temporal regions including the parahippocampus, entorhinal cortex, and hippocampal subfields. Method 27 elderly subjects and 27 young controls were measured olfaction acuity, cognitive function, and structural magnetic resonance imaging. Image processing and gray matter volumetric segmentation were performed with FreeSurfer. Volume data were analyzed with SPSS Statistics software. Results Interesting results of this study were that volume reduction in the entorhinal cortex was not directly linked with declining olfactory ability. Volume reduction in the left entorhinal cortex was correlated with volume reduction in the left parahippocampus and dentate gyrus. However, left parahippocampus volume reduction had the greatest impact on olfactory decline, and the entorhinal cortex and dentate gyrus might additionally contribute to olfactory decline. Conclusion Our results indicate that olfactory decline may be directly reflected in the medial temporal regions as reduced parahippocampus volumes, rather than as morphological changes in the entorhinal cortex and hippocampus. The parahippocampus may play an important role in the association between memory retrieval and olfactory identification., Left: Visualization of brain segmentation in a single subject with FreeSurfer. The entorhinal cortex (ENT) is indicated in red, and the parahippocampus (para‐HI) is indicated in green. Right: Visualization of hippocampal subfield segmentation in a single subject with each subfield represented by a different color.

The Proustian memory effect—that fragrances elicit more emotional and evocative memories than other memory cues—is well established. Fragrances also potentiate a variety of psychological states from moods to motivated behavior. Consumer research has shown that pleasant, product-congruent scents enhance product appeal, that products with greater emotional and cognitive involvement are perceived more positively, and that scent can increase recall for product information. However, the effect of Proustian memories on product perception has never been examined. The aim of the present study was to address this issue. An extensive pilot test in which the methods for the main experiment were established was first conducted. The main experiment then tested how a product (body lotion) that varied in fragrance pleasantness and Proustian memory potency was perceived. Data analyses from a nationwide study showed that if the lotion fragrance was perceived as very pleasant, and it evoked potent personal emotional memories, that lotion was liked better and judged to be superior on a variety of functional and emotional attributes than the same lotion whose scent was perceived as equally pleasant but was not experienced as evocative. Our findings demonstrate that it is the personal potency of Proustian memories evoked by a product’s fragrance, more than the hedonic qualities of the scent per se, that drives product perception and has important implications for the development of scented products.

Chronic graft-versus-host disease (GVHD) remains a major late complication of allogeneic bone marrow transplantation (BMT). In a previous study, impaired thymic negative selection of the recipients permitted the emergence of pathogenic T cells that cause chronic GVHD using MHC class II-deficient (H2-Ab1 KO) B6 into C3H model and CD4+ T cells isolated from chronic GVHD mice caused chronic GVHD when administered into the secondary recipients. In this study, we evaluated the kinetics of regulatory T cell (Treg) reconstitution in wild type B6 into C3H model. After myeloablative conditioning, host Tregs disappeared rapidly, followed by expansion of Tregs derived from the donor splenic T cell inoculum. However, the donor splenic T cell–derived Treg pool contracted gradually and was almost completely replaced by newly generated donor bone marrow (BM)-derived Tregs in the late post-transplantation period. Next, we compared the effects of cyclosporine (CSA) and mammalian target of rapamycin (mTOR) inhibitors on Treg reconstitution. Administration of CSA significantly impaired Treg reconstitution in the spleen and thymus. In contrast, BM-derived Treg reconstitution was not impaired in mTOR inhibitor-treated mice. Histopathological examination indicated that mice treated with CSA, but not mTOR inhibitors, showed pathogenic features of chronic GVHD on day 120. Mice treated with CSA until day 60, but not mTOR inhibitors, developed severe chronic GVHD followed by adoptive transfer of the pathogenic CD4+ T cells isolated from H2-Ab1 KO into C3H model. These findings indicated that long-term use of CSA impairs reconstitution of BM-derived Tregs and increases the liability to chronic GVHD. The choice of immunosuppression, such as calcineurin inhibitor-free GVHD prophylaxis with mTOR inhibitor, may have important implications for the control of chronic GVHD after BMT.

Breathing plays an important role in perception of odors and the experience of emotions. We used the dipole tracing method to analyze brain areas related to odor-induced autobiographical memory and emotions estimated from averaged electroencephalograms triggered by inspiration onset during odor presentation. Odor stimuli were perfumes subjects named that elicited a specific, pleasant and personal memory as well as two pleasant odors for controls. The perfumes induced specific emotional responses during memory retrieval, arousal level of the memory, feelings of pleasantness and a sense of familiarity with the odor. Respiration measurement indicated that tidal volume increased and respiratory frequency decreased during presentation of perfume stimuli, showing a deep and slow breathing pattern. Throughout the olfactory stimulation, electroencephalograms and respiration were simultaneously recorded. In the averaged potentials, low frequency oscillation was phase-locked to inspiration. Dipole analysis showed that perfumes activated more widespread areas of the right parahippocampal cortex and converged in the right amygdala compared to control odors. Slow breathing synchronized with odor-induced autobiographical memory and emotions may be subconsciously stored in the parahippocampal cortex and amygdala.

An important feature of olfactory perception is its dependence on respiratory activity. By inspiration, olfactory information ascends directly to olfactory-related limbic structures. Therefore, every breath with odor molecules activates these limbic areas associated with emotional experience and memory retrieval. We tested whether odors associated with autobiographical memories can trigger pleasant emotional experiences and whether respiration changes during stimulation with these odors. During presentation of odors related to autobiographical memories and control odors, we measured minute ventilation, tidal volume, respiratory frequency, O2 consumption, and end tidal CO2 concentration. Findings showed that autobiographical memory retrieval was associated with increasing tidal volume and decreasing respiratory frequency more than during presentation of control odors. Subjective feelings such as emotional arousal during retrieval of the memory, arousal level of the memory itself, or pleasantness and familiarity toward the odor evoked by autobiographical memory were more specific emotional responses compared with those related to control odors. In addition, high trait anxiety subjects responded with a stronger feeling of being taken back in time and had high arousal levels with tidal volume increases. We discussed assumptions regarding how deep and slow breathing is related to pleasantness and comfortableness of an autobiographical memory.

岡山大学病院では，1998年に本邦初の生体肺移植が行われて以降2009年3月までに52例の生体肺移植と15例の脳死肺移植の計67例の肺移植が行われた．特に脳死肺移植では，限られた時間内に血液製剤を準備する必要があり，これまでの肺移植における血液製剤使用量から術前準備量について検討を行った． 赤血球製剤の平均準備量は57.4U，平均使用量は33.5U，C/T比（交差試験単位数/輸血血液単位数）1.73であった．FFPの平均準備量は43.3U，平均使用量は19.4Uで，PCの平均準備量は27.7U，平均使用量は19.8Uであった．両肺移植の平均血液使用量が，赤血球製剤37.9U，FFP 21.8U，PC 22.8Uであったのに対し，片肺移植の平均血液使用量は，赤血球製剤11.5U，FFP 7.0U，PC 4.5Uで有意差が認められた．また，赤血球製剤を100U以上準備した症例が5例あり，全て両肺移植で，うち3例が脳死移植であった． 肺移植では，症例毎の癒着の程度の相違等で一律の血液準備量の決定は難しいと考えられるが，今回の肺移植における血液製剤使用量の検討から血液の必要量については，両肺移植か片肺移植であるか，恐らく，人工心肺の使用の有無が大きな因子であることが示唆された．また，緊急の脳死肺移植や大量の血液製剤準備に対応できるよう，日常的に異型適合血の選択を含めた緊急時の対応と診療科等との連携を深めることが必要であると考えられた．

How can people imagine colors from smelling odors? We assumed that when people can name an odor correctly, they can imagine an appropriate color of the odor source through semantic imagery. The participants smelled 20 everyday odors and for each one chose imagined color from a hue-circle of 24 colors. They also named odors whenever they could. Only 8 odors could be associated with each color-category, and many of the 8 were named easily. However, people also could imagine colors from odors, whether the odors could be named or not. From this we can suggest that people would associate an odor with some inner semantic representations, even if they can't name the odor, then they could imagine colors in accordance with the representations.

特定悪臭物質の酢酸エチル，硫化水素，アンモニアについて，臭気への認知要因を教示で実験操作して，臭気の快不快度への影響度合いを調べた．実験では，臭気の濃度と提示時間を制御して提示し，実験参加者がスライドバーによって連続的に評定した強度応答をリアルタイムで収録する臭気順応計測システムを用いた．154人の実験参加者は，提示される臭気について「健康によい」「健康に悪い」「どちらでもない」のうち，どれかひとつの教示を受けた直後，いずれかの悪臭の感覚的強度を10分間リアルタイムで評定し，終了後，快不快度を評価した．その結果，特定悪臭物質の快不快度においても，教示の影響が現れたが，影響の程度は悪臭物質やその濃度によって異なった．酢酸エチルでは教示の効果が有意で，「健康によい」というポジティブ教示群は，「健康に悪い」というネガティブ教示群よりも快に感じた．硫化水素では，低濃度の場合にのみ，教示の効果がみられ，ネガティブ教示群はポジティブ教示群よりも，また，コントロール教示群はポジティブ教示群よりも不快に評定された．アンモニアについては教示要因の影響はみられなかった．これらの結果は，公害臭気の対策で難題であった快不快の個人差の問題の解明に一歩踏み込むことができた．今後，臭気に対する順応過程の個人差やそれに関わる認知的要因を考慮することによってより実情に則した臭気対策が期待される．

We investigated the features of olfactory mental images by comparing odour images with perceptual and semantic representations. Participants who were assigned to three groups made similarity judgments about 17 common odours by smelling odours, imagining odours, or on the basis of the meaning of odour source names. In the smelling group, every pair of odours was compared. In the imagining group, imagined odours were compared twice, both before and after associative learning of the odour/name combinations. In the meaning group, the odour source names were compared in terms of general word meanings. Nonmetric multidimensional scaling analysis was applied to each group of similarity data and three-dimensional sensory, mental, and semantic spaces were composed. 17 elements in the mental and semantic spaces were super-imposed onto the sensory space by Procrustes rotation. We found that the averaged distances of the 17 elements between the sensory and the mental spaces (either before or after learning) were smaller than those between the sensory and semantic spaces. We suggest that odour images have sensory features, especially after associative learning between perceived odours and their names.

Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-γ–deficient and IL-17–deficient mice as donors. Infusion of IFN-γ−/− or IL-17−/− T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-β expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD.

Allogeneic hematopoietic stem cell transplantation (HSCT) is used effectively to treat a number of hematological malignancies. Its beneficial effects rely on donor-derived T cell-targeted leukemic cells, the so-called graft-versus-leukemia (GVL) effect. Induction of GVL is usually associated with concomitant development of graft-versus-host disease (GVHD), a major complication of allogeneic HSCT. The T cells that mediate GVL and GVHD are activated by alloantigen presented on host antigen-presenting cells of hematopoietic origin, and it is not well understood how alloantigen expression on non-hematopoietic cells affects GVL activity. Here we show, in mouse models of MHC-matched, minor histocompatibility antigen-mismatched bone marrow transplantation, that alloantigen expression on host epithelium drives donor T cells into apoptosis and dysfunction during GVHD, resulting in a loss of GVL activity. During GVHD, programmed death-1 (PD-1) and PD ligand-1 (PD-L1), molecules implicated in inducing T cell exhaustion, were upregulated on activated T cells and the target tissue, respectively, suggesting that the T cell defects driven by host epithelial alloantigen expression might be mediated by the PD-1/PD-L1 pathway. Consistent with this, blockade of PD-1/PD-L1 interactions partially restored T cell effector functions and improved GVL. These results elucidate a previously unrecognized significance of alloantigen expression on non-hematopoietic cells in GVL and suggest that separation of GVL from GVHD for more effective HSCT may be possible in human patients.

Umbilical cord blood transplantation (CBT) has increasingly been used as a therapeutic option for adult patients for whom allogeneic stem-cell transplantation is not indicated, due to the availability of cord blood. However, myeloablative conditioning regimens are associated with significant mortality, and high relapse rates in reduced-intensity regimens may result in a poor rate of disease-free survival for those with advanced stages of hematological malignancies. Therefore, it remains unknown whether CBT is a truly effective option for such adults with high-risk disease, as well as for those with standard-risk disease.Thirty adult patients with a median age of 45 years (range: 16-67) with standard or high-risk disease underwent CBT from unrelated donors at Okayama University Hospital between October 2002 and May 2007. Twenty-one patients had diseases classified as high-risk for transplantation. The median number of nucleated cells in infused cord blood was 2.65 x 10(7)/kg (range: 1.73-4.87).Twenty-three patients achieved neutrophil engraftment at a median time of 22 days (range: 13-42) after CBT. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 53.6% . Out of the 30 patients, 11 were alive and disease-free at a median time of 446 days (range: 124-1153) after CBT. The cumulative 1-year overall survival in patients with standard-risk or high-risk disease was 63.5% and 15.4%, respectively (p=0.01).Although from a retrospective study, these results suggest that unrelated donor CBT could be safe and effective for adult patients with standard-risk disease who cannot find a suitable HLA-matched volunteer marrow or peripheral blood donor.

Abstract 1902 Several clinical and experimental studies have reported that a recently developed intra-bone marrow (IBM) stem cell transplantation (SCT) technique gives high rates of engraftment and is associated with a low incidence of acute graft-versus-host disease (GVHD). Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality and remains a major obstacle after allogeneic SCT. In the present study, the extent of IPS after IBM-SCT was compared with that after conventional intravenous SCT (IV-SCT) using a lethally irradiated B6(H-2b) into F1 (H-2b/d) mouse IPS model. Compared with IV-SCT, IBM-SCT significantly improved the clinical GVHD score and reduced total and CD3+ T cell numbers in bronchoalveolar lavage fluid (9.6± 3.5 vs. 21.3 ± 0.5 x104/ml; p < 0.05). Histopathological examination of lung tissue at 6 weeks post-SCT showed significantly reduced IPS pathology in mice that underwent IBM-SCT. To explore the mechanisms of the reduction in IPS pathology in mice that underwent IBM-SCT, we monitored the in vivo distributions of infused donor cells and compared them between mice that underwent IBM-SCT versus IV-SCT. Recipient mice were imaged at different time points (1, 2, 3, and 6 h, and 1, 2, 3, and 5 days), using a lethally irradiated luciferase-expressing transgenic FVB/N (FVB/N luc+)(H-2q) into BALB/c (H-2d) mouse model. In vivo bioluminescence imaging (BLI) analysis revealed that the majority of injected donor cells were trapped in the lung 1 h after IV-SCT. In contrast, almost all donor cells were localized in the injected limbs 1 h after IBM-SCT, and significantly fewer cells had reached the lung (3.1± 0.7 vs. 16.7± 1.1 x105 photons/sec/animal, IBM-SCT vs. IV-SCT, p < 0.01; Figure). After syngeneic (FVB/N luc+ into FVB/N) SCT, the majority of the injected cells were also trapped in the lung 1 h after IV-SCT, and a similar difference was observed in donor cell distribution in the lung after IV-SCT versus IBM-SCT (2.4± 0.6 vs. 11.6± 1.3 x105 photons/sec/animal; p < 0.01). These results suggest that initial cell localization to the lung is dependent on the SCT method. At 2 days post-SCT, we examined the profiles of chemokines produced locally in the lung (CCL2, CCL3, CXCL1, CCL5, and CCL8). The mRNA expression of CC chemokines, especially CCL2, was more strongly induced in the lung after allogeneic IV-SCT than after allogeneic IBM-SCT (0.098 ± 0.020 vs. 0.020 ± 0.003 units/GAPDH mRNA; p < 0.05). A similar difference was observed between mice that underwent syngeneic IV-SCT and syngeneic IBM-SCT, suggesting that increases in chemokine levels in the lung early post-SCT are also dependent on the SCT method. At 5 days post-syngeneic SCT, BLI analysis revealed that no difference was observed in donor cell distribution in the lung after IV-SCT versus IBM-SCT (4.8± 1.1 vs. 4.6± 2.5 x107 photons/sec/animal; p =0.94). On the other hand, the BLI signals dramatically increased in the lungs of mice that had undergone allogeneic IV-SCT after day 2 post-SCT and there was a significant difference in the BLI signals between IV-SCT and IBM-SCT mice at 5 days post-SCT (50.9± 6.6 vs. 16.0± 6.2×107 photons/sec/animal; p < 0.05). These results suggest that increases in chemokine levels in the lung at day 2 post-SCT lead to increases in the allogeneic response in the lung. In summary, we have shown that the initial localization of donor cells to the lung and increases in lung chemokine levels are dependent on the SCT method. The targeting of donor cell trafficking to the lung may be a promising strategy for preventing IPS, and IBM-SCT may reduce IPS after allogeneic SCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 727 Chronic graft-versus-host disease (cGVHD) remains a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, and the treatment of cGVHD remains challenging. All-trans retinoic acid (ATRA), a potent derivative of vitamin A, can regulate immune responses. Am80, which has biological activity approximately 10 times more potent than that of ATRA by binding to RARα and RARβ, but not RARγ, also reduces the severity and progression of immune disease models, including contact dermatitis, collagen-induced arthritis, allergic encephalomyelitis, and atherosclerosis models. Am80 has been reported to suppress the differentiation of Th17 and Th1 cells. Previously, we demonstrated that the administration of ATRA or Am80, significantly decreased skin fibrosis and alopecia, a dominant feature of cutaneous cGVHD, using a well-characterized experimental model of cGVHD: B10.D2 (H−2d) → BALB/c (H−2d). Flow cytometry analysis of the peripheral lymph nodes (PLNs) on day 16 showed significant reductions in Th1, Th17, and Foxp3+ regulatory T cells (Tregs) in Am80-treated recipients, as compared to controls, whereas no reduction in Th2 cells was observed (Nishimori et al., 2009 ASH). To further investigate the roles of Th17 cells and other Th subsets (Th1 and Th2) in cGVHD, we first assessed the kinetics of Th cytokines in the B10.D2 (H-2d) → BALB/c (H-2d) model of cGVHD, which reflects the clinical and pathological symptoms of human cGVHD. BALB/c mice were subjected to sublethal irradiation (6.75 Gy) and injected with 8 × 106 T-cell-depleted bone marrow cells and 8 × 106 spleen cells or 2 × 106 CD90+ spleen T cells from B10.D2 mice. In the early phase (day 14) of post bone marrow transplant (BMT), donor T cells produced significantly less IL-17 in the PLNs of recipients in allogeneic BMT than in syngeneic BMT (1.68±0.09% vs. 4.30±0.53%, p Disclosures: No relevant conflicts of interest to declare.

Abstract 4487 Chronic graft-versus-host disease (cGVHD) remains a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, and the treatment of cGVHD remains challenging. All-trans retinoic acid (ATRA), a potent vitamin A derivative, can regulate immune responses. Synthetic retinoid Am80, which shows biological activity approximately 10 times more potent than that of ATRA by binding to RARα and RARβ, but not RARγ, also reduces the severity and progression of immune disease models, including those for contact dermatitis, collagen-induced arthritis, allergic encephalomyelitis, and atherosclerosis. We hypothesized that the administration of ATRA or Am80 could modulate cGVHD. BALB/c (H-2d) mice were subjected to sublethal irradiation and injected with 8 × 106 T-cell-depleted bone marrow cells and 8 × 106 spleen cells from major histocompatibility complex-matched, multiple minor histocompatibility antigen-mismatched B10.D2 (H-2d) mice. Then, the mice were given oral ATRA (200 μg/body), Am80 (1.0 mg/kg body weight), or vehicle daily, beginning from day 0. ATRA slightly decreased the clinical cGVHD score, whereas Am80 significantly reduced the score (Table). When administered daily, Am80 decreased the clinical score beginning from day 21, as in a treatment setting (data not shown). Histopathological examination of the skin showed significantly reduced GVHD pathology in recipients of Am80 (Table). Flow cytometry analysis of the peripheral draining lymph nodes on day 16 showed significant reductions in IFN-γ+, IL-17+, and Foxp3+ cells in Am80-treated recipients compared to controls (Table), whereas no reduction in IL-13+ cells was observed. Cytometric bead arrays and enzyme-linked immunosorbent assays (ELISA) revealed decreased levels of the cytokines IFN-γ, IL-17, TNF-α, and IL-6 in the supernatant of peripheral lymph nodes from Am80-administered recipients (data not shown). Real-time RT-PCR of ears from these recipients on day 21 showed that the administration of Am80 reduced the expression of Foxp3 and TGF-β (Table and data not shown). Therefore, the administration of retinoids ameliorates cGVHD by reducing Th1 and Th17 inflammatory cytokines and the fibrosis factor TGF-β. Thus, treatment with retinoids may be effective for prophylaxis and treatment of cGVHD. Disclosures: No relevant conflicts of interest to declare.

Chronic graft-versus-host disease (GVHD) is the most common complication in the late stage after allogenic hematopoietic-stem-cell-transplantation (SCT), but the pathophysiology and treatment strategy of chronic GVHD remain poorly defined. Prolonged administration of cyclosporine (CSA) did not decrease the risk of chronic GVHD. Recent studies using a mouse model have shown that regulatory T cells (Tregs) can influence immune responses, and Tregs in the grafts can prevent acute GVHD when injected together with donor T cells. However, it is not known whether Tregs remain in the grafts in the late stage of SCT and play a role in preventing chronic GVHD. First, we examined the origin of Tregs using a major histocompatibility complex (MHC) mismatched mouse SCT model. Lethally irradiated C3H/HeN(H-2k) recipient mice received 10x106 T-cell-depleted bone marrow (BM) cells from B6.Ly-5a(H-2b, CD45.1) mice and 1x106 spleen cells from C57BL/6(B6, H-2b, CD45.2) mice. Spleen cells were collected from SCT recipient mice at serial time points and subjected to fluorescence-activated cell sorting (FACS) analysis. Transplanted mice displayed complete donor hematopoietic chimerism and mild acute GVHD at day14. On day 21 (early stage) after SCT, host type Tregs (CD4+FoxP3+ H-2k) were no longer detectable, and most of the Tregs (83±3%) were derived from donor spleen Tregs (H-2b, CD45.2). However, the homeostatic expansion of spleen Tregs gradually contracted and newly arising donor BM-derived Tregs (H-2b CD45.1) became dominant (93.8±0.5%) in the late stage of SCT (day 120). As in the spleen, BM-derived Tregs reconstitution in the late stage was seen in the thymus and mesenteric lymph nodes. Moreover, in a minor MHC-mismatched SCT model (B6 into C3H.SW), Tregs in the late stage were derived from donor BM cells (97.0±0.2%). These BM-derived Tregs suppress alloreactivity in the same manner as naturally occurring Tregs isolated from naïve mice in the MLR. Next, we compared the effects of CSA and the mTOR inhibitor rapamycin (RAPA) on Tregs reconstitution. Mice receiving CSA or RAPA showed the same Tregs reconstitution pattern: in the early and late stages, Tregs were derived from donor spleen and BM cells, respectively. However, the number of Tregs in the spleen was reduced significantly in mice receiving CSA, as compared to control mice receiving phosphate-buffered saline (PBS; 1.3±0.2x106 vs. 2.4±0.6x106) at day 110. In particular, the number of Tregs in the thymus was reduced dramatically in mice receiving CSA (0.7±0.2 x105 vs. 2.6±0.5x105 , P Our findings indicate that a) Tregs cannot remain in grafts in the late stage, and newly arising donor BM-derived Tregs became dominant; b) CSA hampers BM-derived Tregs reconstitution and may be associated with the development of chronic GVHD; and c) mTOR inhibitors do not hamper Tregs reconstitution and might prove beneficial for the treatment of both acute and chronic GVHD. Figure Figure

Background: Unrelated cord blood transplantation (CBT) has emerged as an effective therapy for treating patients with advanced or high-risk hematologic diseases who have no suitable related or unrelated donor. In older patients or those with extensive prior therapy or other clinical features, nonmyeloablative regimens have been used to reduce the risk of regimen-related toxicity and transplantation-related mortality (TRM). Several studies have been reported on the use of unrelated CBT using various reduced-intensity conditioning regimens. Objectives: This study aimed to evaluate the safety and efficacy of unrelated CBT after nonmyeloablative conditioning using fludarabine, cyclophosphamide and single fraction of total body irradiation of 200 cGy, compared with bone marrow transplantation (BMT) or peripheral blood stem-cell transplantation (PBSCT) for adult Japanese patients with hematologic diseases and relate those to biological and procedural factors. Patients and Methods: Clinical data were collected retrospectively on 70 adults with hematologic disease who received unrelated CBT (n=19) or BMT from unrelated donors (n=27), or PBSCT from related donors (n=24) between August 2000 and June 2008 in our institution. All patients received nonmyeloablative conditioning regimens including fludarabine. The median period of follow-up for survivors was 253 days after CBT, 364 days after BMT and 692 days after PBSCT, respectively. We analyzed the hematopoietic recovery, incidence of graft-versus-host disease (GVHD), risks of TRM and relapse, and disease-free survival (DFS) using Cox proportional hazards models. Results: Comparisons of characteristics in 3 groups showed similar distributions for age, gender ratio, diagnosis, risk of disease at the transplant. Compared with BMT and PBSCT (BMT/PBSCT) recipients, CBT recipients had more previous history of hematopoietic stem cell transplantation (HSCT), less human leukocyte antigen-matched donor and less methotrexate (MTX)-containing GVHD prophylaxis. Multivariate analysis demonstrated slow neutrophil (P Conclusion: These data suggest that unrelated cord blood (UCB) after this nonmyeloablative conditioning could be a safe and effective stem cell source similar to bone marrow or mobilized peripheral blood for adult Japanese patients, and also support the use of UCB as a strategy for extending the availability of transplantation therapy, particularly for older patients without suitable related or unrelated blood or bone marrow donor.

Immunity in chickens with killed organisms of Mycoplasma gallisepticumwas evaluated according to the lesion grade of airsacculitis, the retention of M. gallisep-ticum in organs and histopathological findings. Killed M. gallisepticum did not provideany resistance when intramuscularly administered either alone or in admixture withadjuvants. An increased resistance to infection, however, was observed when it was administered into the respiratory tract in a form of aerosol or by intratracheal injection.A partial immunity was maintained at a significant level for at least 3 months. Theseresults suggest that protection of chickens against M. gallisepticum infection may be pos-sible when the killed vaccine is applied directly to the lower respiratory tract of thechickens. The suggestion is supported by the histopathological findings of specimens col-lected from immunized birds. Little correlation was seen between serological serum titerand resistance to challenge.