Neuropilins (NRPs) are non-tyrosine kinase cell surface glycoproteins expressed in all vertebrates and widely conserved across species. The two isoforms, such as neuropilin-1 (NRP1) and neuropilin-2 (NRP2), mainly act as coreceptors for class III Semaphorins and for members of the vascular endothelial growth factor family of molecules and are widely known for their role in a wide array of physiological processes, such as cardiovascular, neuronal development and patterning, angiogenesis, lymphangiogenesis, as well as various clinical disorders. Intriguingly, additional roles for NRPs occur with myeloid and lymphoid cells, in normal physiological as well as different pathological conditions, including cancer, immunological disorders, and bone diseases. However, little is known concerning the molecular pathways that govern these functions. In addition, NRP1 expression has been characterized in different immune cellular phenotypes including macrophages, dendritic cells, and T cell subsets, especially regulatory T cell populations. By contrast, the functions of NRP2 in immune cells are less well known. In this review, we briefly summarize the genomic organization, structure, and binding partners of the NRPs and extensively discuss the recent advances in their role and function in different immune cell subsets and their clinical implications.

https://digitalcommons.unmc.edu/cgi/viewcontent.cgi?article=1116&context=com_bio_articles

Multifaceted Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy.

Initially found expressed in neuronal and then later in endothelial cells, it is well established that the transmembrane glycoproteins neuropilin-1 (NRP1) and neuropilin-2 (NRP2) play essential roles in axonal growth and guidance and in physiological and pathological angiogenesis. Neuropilin expression and function in epithelial cells has received little attention when compared with neuronal and endothelial cells. Overexpression of NRPs is shown to enhance growth, correlate with invasion and is associated with poor prognosis in various tumour types, especially those of epithelial origin. The contribution of NRP and its ligands to tumour growth and metastasis has spurred a strong interest in NRPs as novel chemotherapy drug targets. Given NRP's role as a multifunctional co-receptor with an ability to bind with disparate ligand families, this has sparked new areas of research implicating NRPs in diverse biological functions. Here, we review the growing body of research demonstrating NRP expression and role in the normal and neoplastic epithelium.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2613.2012.00810.x

Neuropilins: expression and roles in the epithelium.

Regulatory T cells (Tregs) are an immunosuppressive subgroup of CD4+ T cells which are identified by the expression of forkhead box protein P3 (Foxp3). The modulation capacity of these immune cells holds an important role in both transplantation and the development of autoimmune diseases. These cells are the main mediators of self-tolerance and are essential for avoiding excessive immune reactions. Tregs play a key role in the induction of peripheral tolerance that can prevent autoimmunity, by protecting self-reactive lymphocytes from the immune reaction. In contrast to autoimmune responses, tumor cells exploit Tregs in order to prevent immune cell recognition and anti-tumor immune response during the carcinogenesis process. Recently, numerous studies have focused on unraveling the biological functions and principles of Tregs and their primary suppressive mechanisms. Due to the promising and outstanding results, Tregs have been widely investigated as an alternative tool in preventing graft rejection and treating autoimmune diseases. On the other hand, targeting Tregs for the purpose of improving cancer immunotherapy is being intensively evaluated as a desirable and effective method. The purpose of this review is to point out the characteristic function and therapeutic potential of Tregs in regulatory immune mechanisms in transplantation tolerance, autoimmune diseases, cancer therapy, and also to discuss that how the manipulation of these mechanisms may increase the therapeutic options.

/pdf/the-therapeutic-potential-of-regulatory-t-cells-challenges-z6h8wr0c9y.pdf

The Therapeutic Potential of Regulatory T Cells: Challenges and Opportunities.

Several mechanisms of immune suppression have been attributed to Foxp3+ T regulatory cells (Treg) including modulation of target cells via inhibition of cell proliferation, alteration of cytokine secretion, and modification of cell phenotype, among others. Neuropilin-1 (Nrp1), a co-receptor protein highly expressed on Treg cells has been involved in tolerance-mediated responses, driving tumor growth and transplant acceptance. Here, we extend our previous findings showing that, despite expressing Foxp3, Nrp1KO Treg cells have deficient suppressive function in vitro in a contact-independent manner. In vivo, the presence of Nrp1 on Treg cells is required for driving long-term transplant tolerance. Interestingly, Nrp1 expression on Treg cells was also necessary for conventional CD4+ T cells (convT) to become Nrp1+Eos+ T cells in vivo. Furthermore, adoptive transfer experiments showed that the disruption of Nrp1 expression on Treg cells not only reduced IL-10 production on Treg cells, but also increased the frequency of IFNγ+ Treg cells. Similarly, the presence of Nrp1KO Treg cells facilitated the occurrence of IFNγ+CD4+ T cells. Interestingly, we proved that Nrp1KO Treg cells are also defective in IL-10 production, which correlates with deficient Nrp1 upregulation by convT cells. Altogether, these findings demonstrate the direct role of Nrp1 on Treg cells during the induction of transplantation tolerance, impacting indirectly the phenotype and function of conventional CD4+ T cells.

/pdf/cd4-foxp3-t-regulatory-cells-promote-transplantation-26xpqvg3g8.pdf

CD4+Foxp3+T Regulatory Cells Promote Transplantation Tolerance by Modulating Effector CD4+ T Cells in a Neuropilin-1-Dependent Manner.

Neuropilin-1 + regulatory T cells promote skin allograft survival and modulate effector CD4 + T cells phenotypic signature

Neuropilin-1+ regulatory T cells promote skin allograft survival and modulate effector CD4+ T cells phenotypic signature.

Objective Recent work has suggested that neuropilin-1 (NRP-1) is a surface marker of regulatory T cells (Treg). However, no further relative evidence has been provided to confirm this finding. Since Treg should decline during rejection, the expression of NRP-1 on lymphocytes should decline in a rejected graft. To test this proposal, we examined NRP-1 expression in kidney graft biopsies. Materials and Methods Tissue samples were obtained from 20 kidney graft biopsies with pathologically confirmed acute rejection and from 10 without rejections. We performed immunohistochemistry assays using an anti-NRP-1 monoclonal antibody. The positive cells were counted and the ratios among lymphocytes analyzed. Results Compared with samples from nonrejected graft biopsies (18.71 ± 20.60), the number of positive cells among lymphocytes in the rejected samples showed a lower percentage (3.16 ± 1.72; P Conclusions NRP-1 has an important role in directing the growth of nervous synapses and immune synapses. We found in rejected grafts that the percentage of NRP-1 positive cells among lymphocytes decreased significantly. Therefore, NRP-1 may have a previously unrecognized role to predict the immune state of the graft as a potential marker for Treg.

Expression of neuropilin-1 in kidney graft biopsies: what is the significance?

Voriconazole remains the mainstay for the treatment of invasive fungal infections in heart transplant patients and can significantly increase tacrolimus exposure because of drug‐drug interaction (DDI). However, the magnitude of this DDI is highly variable and difficult to predict. The purpose of this study was to present the characteristics of the DDI between tacrolimus and voriconazole, and further identify the various predictors of tacrolimus dose modification.

The importance of CYP2C19 genotype in tacrolimus dose optimization when concomitant with voriconazole in heart transplant recipients

Aims: Voriconazole is the mainstay for the treatment for invasive fungal
infections in heart transplant patients and significantly increase
tacrolimus exposure because of drug-drug interaction (DDI). However, the
magnitude of this DDI is highly variable and hard to predicted. The
purpose of this study was to present the characteristics of DDI between
tacrolimus and voriconazole, and further identify the predictors of
tacrolimus dose modification. Methods: We retrospectively enrolled 69
heart transplant recipients without using voriconazole as the control
and 68 patients received voriconazole treatment in voriconazole group.
CYP3A4*1G, CYP3A5*3 and CYP2C19*2 or *3 were genotyped by Sanger
sequencing. The requirement of tacrolimus dose for therapeutic
concentrations and tacrolimus dose-corrected trough concentration (C0/D)
before and after VRC administration were evaluated. Results: The DDI
between tacrolimus and voriconazole was in a large inter-individual
variability with more than ten-fold changes in tacrolimus dose (range
1.28–13.00) and C0/D (range 1.43–13.75). Besides, the fold changes of
tacrolimus dose were associated with CYP2C19 genotype, which was
significantly lower in CYP2C19 extensive metabolizers than that in
CYP2C19 intermediate metabolizers or poor metabolizers (4.06±1.85 vs
5.49±2.47, p=0.0031). While no significant difference was found in both
CYP3A4 and CYP3A5 genotypes. Moreover, CYP2C19 genotype and hematocrit
were independent predicting factors for tacrolimus dose modification
after voriconazole co-therapy. Conclusions: This study provided a
potential basis for comprehensive factors to adjust tacrolimus dosage
when co-administrated with voriconazole in individual patients. CYP2C19
genotype and hematocrit should be considered in tailoring tacrolimus
dose.

Predictors of tacrolimus dose optimization when drug-drug interaction associated with voriconazole in heart transplant recipients

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Expression of neuropilin-1 in kidney graft biopsies: what is the significance?

The importance of CYP2C19 genotype in tacrolimus dose optimization when concomitant with voriconazole in heart transplant recipients

Predictors of tacrolimus dose optimization when drug-drug interaction associated with voriconazole in heart transplant recipients