As shown in Fig. 4, TREM-2-deficient DCs had more I-AbhighCD86high mature cells than WT DCs after CpG DNA and Zymosan stimulation. Importantly, the maturation level of TREM-2-deficient DCs was very similar to that of DAP12-deficient DCs, suggesting that TREM-2 signaling is mediated by DAP12 in BMDCs. We also compared TREM-2-deficient DCs to those deficient in both DAP12 and FcRγ. Similar to what we found for cytokine production, TREM-2-deficient DCs showed less CpG DNA- and Zymosan-induced maturation than DAP12/FcRγ-deficient DCs. Interestingly,

whereas WT, DAP12-deficient and TREM-2-deficient DCs had a similar amount of maturation in the absence of stimulus, DCs lacking both DAP12 and FcRγ consistently had less selleck inhibitor basal maturation even though they had the highest amount of stimulus-induced hypoxia-inducible factor cancer maturation (Fig. 4B). In conclusion, these results show that TREM-2/DAP12 signaling negatively regulates DC TLR responses. It has been reported that Siglec-H is involved in the negative regulation of type I IFN responses through DAP12 signaling in plasmacytoid DCs (pDCs) 20, 21.

Though TREM-2 is not expressed in pDCs (Ito and Hamerman, unpublished data), we hypothesized that TREM-2 may inhibit type I IFN production in conventional DCs, such as BMDCs. We assessed IFN-α4 and IFN-β expression by qRT-PCR in WT and TREM-2-deficient BMDCs after CpG DNA stimulation. Expression of mRNAs encoding both type I IFNs analyzed were higher in TREM-2-deficient BMDCs compared with WT BMDCs at 2 and

6 h after stimulation (Fig. 5A and B). As expected, TREM-2-deficient BMDCs also expressed more mRNA encoding IL-12 p40 (il12b) at 2 and 6 h after CpG DNA treatment than WT BMDCs (Fig. 5C). Intriguingly, IRF7 expression was not changed between WT and TREM-2-deficient BMDCs (Fig. 5D). IRF7 is induced by type I IFN stimulation and plays a major role in the positive feedback regulation of type I IFN expression 22, 23. We also measured IFN-β secretion after 16 h of CpG DNA stimulation by ELISA. TREM-2-deficient BMDCs secreted significantly more IFN-β protein than WT BMDCs after CpG DNA stimulation (Fig. 5E). These results suggest that increased type I IFN response in TREM-2-deficient Megestrol Acetate DCs was due to lack of TREM-2/DAP12 signaling at the primary TLR response phase. In conclusion, these results demonstrate that TREM-2 negatively regulates DC production of type I IFN in addition to IL-12 p70 and TNF in response to TLR ligation. Because TREM-2-deficient BMDCs matured more efficiently than WT BMDCs, we investigated whether the antigen-presenting activity of TREM-2-deficient DCs was higher than that of WT DCs. We co-cultured OVA peptide-pulsed BMDCs in the presence of high (100 nM) and low (25 nM) doses of CpG DNA with CFSE-labeled OT-II TCR transgenic CD4+ T cells for 72 h and detected CFSE dilution of CD4+ T cells by flow cytometry (Fig. 6A).

The authors would like to gratefully acknowledge the substantial contributions of the entire Australian and New Zealand nephrology community (physicians, surgeons, database managers, nurses, renal operators and patients) that provide information to, and maintain, the ANZDATA Registry database. This paper has not been published or submitted for publication elsewhere. All authors have contributed this website to paper: Wai H Lim 70%, Hannah Dent 10%, Steve Chadban, Scott Campbell,

Graeme R Russ and Stephen P McDonald all 5%. “
“To assess the effectiveness of supine/standing urinalysis for differential diagnosis of left renal vein entrapment syndrome (LRVES) combined with or without glomerulopathy. The enrolled patients with abnormal urinalysis and LRVES demonstrated by Doppler sonography were guided to perform a supine/standing urinalysis. Fifty-two patients were enrolled. Most of them were adolescents (aged 14–29 years, 73.1%) and with low body mass index (BMI, mean BMI, 19.8 ± 2.4 kg/m2). Seventeen cases (32.7%) manifested orthostatic urine abnormalities (OUA, proteinuria and/or haematuria show negative in supine while positive after 15 min standing), two patients who had undergone renal biopsies both showed no evidence of kidney lesions, another selleck compound two patients were changed from abnormal to normal urinalysis after weight gain. The remaining 35 cases (67.3%) manifested

non-orthostatic urine abnormalities (NOUA, proteinuria and/or haematuria show positive both in supine and standing), 15 patients had undergone renal biopsies and showed different degrees of glomerulopathy. After prednisone/immunosuppression therapy, four patients with glomerulonephritis were changed from the NOUA to the OUA classification. Statistics analyses showed that serum total protein and albumin

levels were significantly lower (P = 0.028, 0.007, respectively) and urinary protein was significantly higher (P = 0.007) in the NOUA group than in the OUA group. After the indication of LRVES by ultrasound, patients with OUA likely have only LRVES, while patients with NOUA likely also have glomerulopathy. Supine/standing urinalysis combined with Doppler sonography can be helpful for differential diagnosis of LRVES combined with or without glomerulopathy. “
“Myeloma cast nephropathy contributes to high morbidity ever and early mortality associated with the development of end-stage renal disease. Treatment with extended high cut-off haemodialysis coupled with novel anti-myeloma therapies enables significant reduction of serum-free light chains and has been shown to improve renal outcomes. In this case series, medical records of 6 patients who received high cut-off haemodialysis for biopsy-proven cast nephropathy were retrospectively reviewed. Patients received a total of 344 hours of high cut-off haemodialysis and concurrent chemotherapy. Only 50% became dialysis independent following treatment. One patient who achieved sustained remission remained dialysis dependent.

The plate was MAPK inhibitor incubated for 1 h at 37°C. After several washes, anti-MAC

antibody (100 μL/well at 1 : 1500 dilutions in PBS-T) was added. The plate was incubated for 2 h at room temperature. Wells were washed several times with PBS-T followed by the addition of 100 μL of goat anti-rabbit IgG–HRP conjugate (1 : 1500 dilutions). The plate was incubated at room temperature for 90 min. The unbound conjugate was removed, and the wells were washed. Freshly prepared OPD (100 μL/well) was added and incubated for 5–10 min. The reaction was stopped by adding 100 μL of 2·5 m H2SO4. The absorbance was measured at 490 nm. Purified H.c-C3BP was subjected to SDS-PAGE and lightly stained with Coomassie Blue. The gel region around the 14-kDa-stained band was excised with a clean blade and transferred to a 1·5-mL microcentrifuge tube. The gel slice was washed with autoclaved distilled water and sent for mass spectrometry analysis

to TCGA, New Delhi (India), and Prof. Anil Jaiswal, Department of Pharmacology, University this website of Maryland (USA). The enzyme activity was measured by established protocol [19] with minor modifications. The final concentrations of reagents added to cuvettes were as follows: 0·1 m Tris-HCl/0·5 mm EDTA (pH 8·0), 10 mm MgCl2, 0·2 mm NADH, 2 mm ATP, five units of phosphoglycerate kinase, making the final volume to 1 mL. The test sample also had 3-phosphoglyceric acid. The amount of H.c-C3BP and GAPDH added was 1 μg and 1·25 μg, respectively. The decrease in the optical density of the test is measured against that Janus kinase (JAK) of the blank at 340 nm at room temperature for 10–20 min. A blank assay was carried out to ascertain any residual GAPDH activity in PG kinase used. Buffer was substituted for protein in blank as well as test mixture, and the optical density of the test was measured against the blank.

The blank reading was subtracted from the absorbance of the test substance. The enzyme activity was calculated taking the change in absorbance at 340 nm from the initial linear readings. The cDNA sequence of H. contortus GAPDH was retracted from NCBI and used for primer designing. The primers were designed using Gene Tool and DNAStar softwares. EcoR1 (GAATTC) and Hind III (AAGCTT) restriction sites were included at the 5′ ends of the forward and reverse primers, respectively. Standard PCR conditions were used with an annealing temperature of 45°C. Alkaline lysis method was adopted for plasmid isolation. To clone in pPROEX™-HTb expression system, the plasmid and PCR product were digested with restriction enzymes and the products were gel-purified using PrepEase™ Gel Extraction kit (USB, Cleveland, OH, USA). Ligation was carried out at 22°C using T4 DNA ligase. The ligated plasmids were used to transform competent DH5α-E. coli. Plasmids were isolated from the transformed colonies and digested with restriction enzymes to check for the insert release.

JT and MK performed pyrosequencing analysis. CM

and XM participated in the design of the study and helped draft the manuscript. RS helped with statistical analysis. All authors read and approved the final manuscript. This work was supported by grants from French Ministry of Research: Agence Nationale pour la Recherche (ANR) 2010-BLAN-1133 01 and by the Société Française de Rhumatologie (SFR): R. Belkhir Daporinad mw received a research bursary for 2009–2010. “
“We investigated the role of B cell lymphoma (BCL)-2-interacting mediator of cell death (Bim) for lymphocyte homeostasis in intestinal mucosa. Lymphocytes lacking Bim are refractory to apoptosis. Chronic colitis was induced in Bim-deficient mice (Bim–/–) with dextran sulphate sodium (DSS). Weight loss and colonoscopic score were increased significantly in Bim–/– mice compared to SRT1720 supplier wild-type mice. As Bim is induced for the killing of autoreactive cells we determined the role of Bim in the regulation of lymphocyte survival at mucosal sites. Upon chronic dextran sulphate sodium (DSS)-induced colitis, Bim–/– animals exhibited an increased infiltrate of lymphocytes into the mucosa compared to wild-type

mice. The number of autoreactive T cell receptor (TCR) Vβ8+ lymphocytes was significantly higher in Bim–/– mice compared to wild-type controls. Impaired removal of autoreactive lymphocytes in Bim–/– mice upon chronic DSS-induced colitis may therefore contribute to aggravated mucosal inflammation. Pro-survival B cell lymphoma (BCL)-2 interacts with pro-apoptotic BCL-2-interacting mediator of cell death (Bim). Bim is sequestered to microtubules [1], by which Bim can be separated from BCL-2. Upon apoptotic stimuli, such as ultraviolet (UV) irradiation and growth factor withdrawal, Bim translocates Vitamin B12 to BCL-2 and neutralizes its anti-apoptotic activity. This process does not require caspase activity, and therefore constitutes an initiating event in apoptosis signalling. Bim was suggested to have an increased

prevalence of phosphorylation sites. Bim is phosphorylated and targeted for degradation by the proteasome [2]. Inactivation of BCL-2 has been suggested to be the key to the ability of Bim to induce apoptosis. However, an alternative model argues that some forms of Bim can also bind directly to the other pro-apoptotic proteins Bax and Bak in order to initiate apoptosis [3]. Bax and Bak act by forming pores in the mitochondrial membrane, finally triggering apoptosis. Other BH3-only proteins, such as Bmf, Bad, Noxa and Puma, are considered to act as sensitizers which bind the pro-survival BCL-2 protein and thereby displace Bim from BCL-2 to promote cell death [4]. Bim transduces death signals not only after its release from the actin cytoskeleton, but also by activation of its transcription. Bim transcription is induced by transforming growth factor (TGF)-β-driven apoptosis in a number of cell types [5].

By contrast,

the attenuation of signalling in Siglec-G-deficient mice under the same conditions may be insufficient to prevent B-cell activation and antibody secretion. Alternatively, accumulating B1-like B cells in dnRAG1 mice may be intrinsically resistant to (auto)antigenic stimulation. This possibility is supported by experiments showing that B cells from dnRAG1 mice exhibit impaired responses Dorsomorphin price toward antigenic stimuli in vitro and immunization by thymus-independent antigens in vivo (Fig. 3). Whether genetic manipulation of BCR signalling pathways in dnRAG1 mice can promote (auto)antibody production in these animals is a focus of future investigation. Both the B1 and the MZ B-cell populations are known to be enriched for cells with poly-reactive and/or weakly self-reactive BCRs.53 B cells with such specificities could be potentially dangerous if allowed to undergo affinity maturation toward host antigens, but are generally Selleck RG7420 tolerated by the host because of the useful role they play in recognizing bacterial antigens to promote early immune responses against these organisms.45,46

There remains some uncertainty over the extent to which BCR specificity controls lineage specification of B1 B cells.54 The data presented here suggest that splenic B1-like B cells accumulating in dnRAG1 mice acquire this phenotype based on their BCR specificity, because enforced expression of a heavy chain transgene specific for

Farnesyltransferase dsDNA (56Rki) in dnRAG1 mice blocks their accumulation, and instead promotes expansion of MZ-like B cells (Fig. 7). The latter result is particularly interesting in light of evidence showing that anti-dsDNA B cells that fail to edit BCR specificity away from dsDNA, but that possess cross-reactivity toward intracellular antigens, may acquire the phenotype of a B cell found in the MZ and remain sequestered there as a means to escape editing pressure.55 The fact that B cells with a B1 phenotype are normally detected at low levels in the spleen, but are significantly increased in dnRAG1 mice, raises the question of whether B cells normally present in this compartment have been positively selected into this reservoir, or whether this population represents a safe anatomical repository for peripheral B cells that have attempted to undergo receptor editing, but still retain vestiges of self-reactivity at levels that are tolerated by the host. These possibilities are not necessarily mutually exclusive. The selection model of B1 B-cell differentiation argues that if this self-specificity is retained, then the B cell would adopt a B1-like phenotype. The expansion of splenic B1 B cells in dnRAG1 mice suggests that the antigenic specificities represented in this population are tolerated by the host if they cannot be successfully edited.

Structurally, the purpose of the placenta in mammals is to bring maternal and fetal circulatory systems in close proximity to facilitate exchange of nutrients, oxygen, waste, and other factors.[2] Several good reviews of comparative placentation exist.[3-7] Placentae are usually described by the layers existing between fetal trophoblast, which itself envelops fetal vessels and mesenchymal

cells, and maternal blood.[2] The controversy of placentation and the validity of animal models will likely continue because while it is assumed that differences in placentation will lead to different adaptive mechanisms, experimental changing of placentation in certain animals is likely extremely challenging. The human placenta is said to be hemochorial,[2] in that maternal blood is in direct contact with this website fetal trophoblast. There are, however, other points of contact between learn more maternal and fetal tissues, for example in the villous structures that anchor the placenta.[8] The human placenta moreover is said to be interstitial, in that implantation occurs completely within the maternal uterine wall[4] thus allowing for multiple points of interaction between maternal and fetal tissues early in gestation. Primates commonly used in research, for example baboons, macaque, chimpanzee, also have hemochorial placentas[3,

6] with more or less invasion upon implantation, and a villous organization, although this is not true for all primates (e.g. lemurs[3]). The vascular structure of human placenta undergoes a revision in early gestation in which trophoblast lines maternal uterine arteries[9] to allow for maximal blood flow.[10] The placenta in rats (see recent review by Soares et al.[11]) mice, and guinea pigs (rodents) is similar to that in humans

in that maternal blood is in direct contact with trophoblast. There are subtle(?) structural differences between human and rodent placentae, including the flow of blood due to a labyrinthine as opposed to a villous organization, the depth of trophoblast invasion,[6] and the trophoblast subpopulations.[2] For example, an additional layer of trophoblast, the giant cell layer, in addition to cytotrophoblast and syncytital enough trophoblast has led some authors to call the rodent placenta ‘hemotrichorial’. Because of only one trophoblast layer, the guinea pig placenta is sometimes referred to as ‘hemomonochorial’. In addition to structural differences, there are subtle differences in the expression of proteins, such as those involved in immune regulation.[12-15] While the definitive placenta is in place for a short time relative to gestation in mice and rats,[2] the longer gestation in guinea pigs makes this less true. Rabbits belong to the group of mammals called lagomorphs. Their placentas are hemochorial with two trophoblast layers, a syncytium layer and a cytotrophoblast layer, which is similar to humans, but organized in a labyrinthine structure.

Additionally, CFSE-labelled splenic CD4+ T lymphocytes from C57BL/6 mice treated with or without AZM for 3 days were cultured in MLR with allogeneic BALB/c BM-derived mDCs for 3 days. It was confirmed that expression of major histocompatibility complex (MHC) class II and co-stimulatory molecules (CD40, CD80 and CD86) on LPS-induced mDCs was elevated in comparison with imDCs (data not shown). We did not observe any differences in the dividing CFSElow CD4+ population between AZM-treated and untreated C57BL/6 mice in the allogeneic MLR (Fig. 3c). These data indicate that AZM does not inhibit donor lymphocyte functions ex vivo at the tested doses. Novel immunomodulatory agents

focused on NF-κB in host DCs [6-11, 20-22, 31] instead of the Selleck Ipatasertib conventional immunosuppressants targeted on donor T lymphocytes [1-5] have been reported to prevent or attenuate GVHD in allogeneic haematopoietic transplantation, including signaling pathway in the histoincompatible setting. In this study, we used AZM – a macrolide antibiotic and a NF-κB inhibitor of murine DC maturation – alone for GVHD prophylaxis and showed that it inhibited acute GVHD significantly in MHC-incompatible bone marrow transplantation (BMT) without interfering with donor engraftment. AZM is active against a wide variety of bacteria and also acts as an anti-inflammatory agent by modulating the functions of DCs, monocytes

and/or macrophages [24, 35-37]. Previously, Sugiyama et al. [35] and our team [24] have reported that AZM inhibits the maturation and functions of murine bone marrow-derived DCs in vitro. We also showed that AZM, by inhibiting the NF-κB pathway in LPS-stimulated DCs and generating DCs with regulatory DC properties, blocks murine DC–T lymphocyte interaction in allogeneic immune systems [24]. In murine allogeneic

BMT models, recipient-type regulatory DCs, characterized by low expression levels of co-stimulatory molecules, moderate levels of MHC molecules, low production of IL-12, high production of IL-10 and PIK3C2G suppression of NF-κB activity even after stimulation with LPS, inhibited acute GVHD, mediated partly by IL-10, as a key regulator of anti-inflammatory responses [38, 39]. Sato et al. [38] also found that recipient-type regulatory DCs increased donor-type regulatory T cells (Treg) which produced IL-10 and resulted in protection from lethal acute GVHD. Additionally, we reported significantly increased IL-10 levels in co-cultures of allogeneic T lymphocytes and AZM-treated DCs [24]. The precise mechanisms underlying the findings presented in this report are unknown, because we did not analyse induction of Treg and/or plasma IL-10 of recipient mice treated with AZM, or for immunophenotypic or functional changes in DCs derived from recipients treated with AZM due to a numerical problem without in-vivo expansion stimulated with Flt3 ligand and/or other cytokines [11, 40, 41].

Interestingly, a recent report indicates that non-genetic naturally occurring differences in the levels or states of anti- or pro-apoptotic proteins are the primary causes of cell-to-cell variability in timing

and likelihood of apoptotic cell death in cell lines [47]. Of note, TRAIL resistance seems to be even more pronounced when assessing TRAIL activity towards primary patient material. Indeed, TRAIL sensitivity in GBM cell lines does not correlate SB203580 in vivo well with activity towards primary GBM cells. In fact, TRAIL resistance in primary GBM cells appears rather widespread, thus questioning the ultimate clinical benefit of TRAIL as single agent therapy. Intrinsic or acquired resistance to TRAIL can often be overcome by combination of TRAIL-based agents with chemotherapeutics, radiation or other novel therapeutic drugs. Preliminary clinical data also highlight click here the rationale of this approach, with two complete and two partial responses upon co-treatment of a small group of non-Hodgkin lymphoma patients with TRAIL and the anti-CD20 antibody rituximab

[48]. These clinical observations are corroborated by recent in vitro data indicating that combined treatment of cells with rituximab and TRAIL or an agonistic TRAIL-R1 antibody synergistically induced apoptosis [49,50]. Thus, the presence of in vitro synergy may be a useful indicator for potential clinical benefit in combinatorial strategies. Both radiotherapy and chemotherapy have been studied in combination with TRAIL in preclinical studies in a variety of tumour types [51–62]. With regard to GBM, positive results on tumour regression were obtained after combination therapy. This synergy may be due to various points

of crosstalk between TRAIL and chemo/radiation (for overview see Figure 3) including up-regulation of agonistic TRAIL receptors by irradiation [56–58] and chemotherapy [59]. Of note, up-regulation Endonuclease of TRAIL-R2 by chemotherapeutics in TRAIL-resistant GBM cell lines appears to be p53-dependent, with up-regulation of TRAIL-R2 only occurring in p53wt but not p53mut cells [60]. In contrast, others have found no effect on the level of receptor expression after irradiation or chemotherapy [51,61]. Another possible point of synergy is down-regulation of the anti-apoptotic proteins cFLIP and phosphoprotein enriched in diabetes/astrocytes (PED/PEA-15) that both competitively inhibit caspase-8 activation in the death-inducing signalling complex [63]. Systemic in vivo administration of TRAIL with cisplatin synergistically suppressed both tumour formation and growth of established subcutaneous human glioblastoma xenografts in nude mice and also significantly extended the survival of mice bearing intracerebral xenografts compared with single-agent treated mice [59].

The registration fee of the Congress was kept affordably low, taking into consideration the difficult global economic situation and the cuts that have hit the research community in recent years. Fortunately, the meeting received crucial support from 7 government sponsor agencies and 18 private sponsors (http://www.fimsa2012.com). A pre-Congress press meeting was organized on the 14th March to which representatives of leading newspapers and electronic media were invited so that the general public could be briefed about the main features of the Congress. Narinder

Mehra, the President of the Congress and his colleagues gave an overview of the meeting and the importance of immunology in health and disease. Stefan Kaufmann (President of IUIS) spoke about

the importance of vaccines and immunotherapeutics in every day life and Nicholas King (FIMSA President) gave a perspective of the federation and of its various activities. The Congress Osimertinib mw was officially inaugurated by Sir Gustav Nossal (Australia), together with Stefan Kaufmann (President of IUIS, Germany), Nicholas King (FIMSA Presi-dent, Australia), GP Talwar (India), Jacob Natvig (Norway) and the organizers led by Congress President Narinder Mehra (Fig. 1 and 2). The inaugural and keynote address was delivered by Sir Gustav Nossal (Fig. 2A) who spoke on the development status of various vaccines and highlighted that immunology with its impact on human health could help prevent two-thirds of premature deaths, particularly those with an infectious cause. filipin Interestingly while life expectancy at birth 3-MA mw in the more developed world has improved from 70 years in the 1960s to >80 years in 2011, that in African countries (e.g. Zambia) has actually shown a decline from 45 to 39 years. Sir Gustav Nossal advocated the creation of a global fund for vaccine research for the three big diseases AIDS, TB and malaria. Further, he discussed the progress of the RV144 phase II trial of the prime boost vaccine ALVAL prime-AIDS; RTS,S from Glaxo Smith

Kline for malaria; and three vaccines for TB currently in phase II trials namely, AERAS-402 crucell Ad35, MVA85 A/AERAS 485, GSKMT72, a recombinant fusion protein of Agtb 32 and tb 39. The first day of the conference started with a fantastic master lecture on peripheral regulatory T (Treg) cells by Abul Abbas (USA). He described how the immune system adapts to pathogenic inflammatory reactions by generating Foxp3+ve Treg cells in the periphery. A fraction of these cells survive as memory Treg cells and are able to limit subsequent inflammation in the tissue. He also showed that antigens and cytokines are the major stimuli that induce peripheral Treg cells and control their balance with effector cells. This was immediately followed by the second master lecture, which was given by James McCluskey (Australia) on the genetic control of immune response.

In this case, it has not been established whether the long-term residence of the T cells in the sensory ganglion is dependent on prolonged antigen exposure due to continued viral gene expression; however, when we consider the initial site of HSV-1 infection in the skin, it appears that prolonged

antigen exposure is unnecessary to keep memory T cells on site. Scarification of flank skin and infection with HSV-1 is followed BMS-777607 by viral replication in epidermal cells and latent infection of neurons in the local dorsal root ganglia. After the skin lesions heal and virus is no longer detectable, CD8+ T cells specific for HSV-1 remain behind in the epidermis. Subsequent ipsilateral versus contralateral flank rechallenge Microtubule Associated inhibitor with virus reveals that the ipsilateral side is much more resistant to viral replication in the epidermis and this protection is T-cell mediated 14. In this case, it is unlikely that memory T cells are retained in skin due to prolonged antigen presentation

because infectious virus is not produced in the infected neurons to traffic back to the original site of infection. Furthermore, when previously infected skin is grafted to a naïve animal and nerve endings are severed, the HSV-specific T cells remain in the graft 14. Skin-resident CD8+ T cells, unlike memory cells in the spleen, express high levels of integrins CD103 and VLA-1. The known ligand for CD103 is E-cadherin which is expressed at high levels by the epithelial cells. Although HSV-1 does not recrudesce in mice and spread from the latently infected ganglia back to the skin, this model system provides a wonderful example of how adaptive immune memory attempts

these to predict the site of re-entry or reactivation of an infectious agent. Fixed drug eruptions provide intriguing evidence from the clinic that the skin is a patchwork of fixed or sessile resident memory T cells. Observations in some patients show specific skin lesions at reproducible sites on their skin when administered a drug orally 15. The lesions have been described as classic delayed-type hypersensitivity reactions with CD8+ T cells as the mediators but in which the trigger is delivered systemically and the reactive T cells are local. Whether the drug or its metabolites cause the reaction is not known, nor is the identity of the original insult that generates such a fixed site of local memory. In addition to memory cells that remain for extended periods in the epidermis at sites of prior infection, a large fraction of circulating memory T cells expresses the adhesion molecule cutaneous lymphocyte antigen (CLA) which mediates preferential migration into and through the skin. Clark has estimated that 20 billion memory T cells are present in our skin, outnumbering those present in the entire circulation 6. Such tissue-selective homing may be imprinted on the responding T cells in skin-draining lymph nodes.