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Low-risk renal transplant recipients treated with standard immunosuppressive therapy including interleukin-2 receptor (IL-2R) antagonist show a low incidence of early rejection episodes but few reports have examined the incidence and severity of late rejection processes. This study evaluated retrospectively cellular and antibody-mediated rejection (AMR) among 42 recipients selected because they showed low panel-reactive-antibodies, short cold ischemia time, no delayed graft function, and therapy including basiliximab (Simulect) induction. The mean observation time was 6.6 years. Sixty-seven percent of donors were deceased. Ten-year patient and death-censored graft survivals were 81% and 78%, respectively. Seven patients lost their kidneys due to nonimmunologic events. The seven recipients who experienced cellular rejection episodes during the first posttransplant year had them reversed with steroids. Five patients displayed late acute AMR causing functional deterioration in four cases including 1 graft loss. De novo sensitization occurred in 48% of recipients including patients without clinical rejection. In conclusion, long-term follow-up of kidney transplant recipients selected by a low immunologic risk showed a persistent risk of de novo sensitization evolving to acute AMR in 11% of cases. Although immunologic events were related to late immunosuppressive reduction, most graft losses were due to nonimmunologic factors., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We report the case of a 43-year-old patient with HIV infection treated with antiretroviral therapy, which was complicated by immunoglobulin A (IgA) nephropathy and renal failure, who subsequently was transplanted using a deceased donor kidney transplant. During the late posttransplant period we detected specific anti-donor HLA antibodies showing a preserved alloantigen response. A renal biopsy showed no acute cellular or humoral rejection, an absence of pericapillary C4d deposits or SV40 infected cells, but demonstrated IgA mesangial deposits and mild interstitial fibrosis probably related to calcineurin inhibitor toxicity. This case shows that allo- and autoimmune responses are preserved despite immunosuppressive treatment and original HIV disease. It warns of the importance of maintaining optimal monitoring and immunosuppressive strategies among HIV-positive recipients who become solid organ transplant recipients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Dendritic cells (DCs) are professional antigen-presenting cells able to induce immunity or tolerance. The interactions of immature DCs with naive T lymphocytes induce peripheral tolerance through mechanisms that include anergy or deletion of lymphocytes or the generation of regulatory T cells. Because of the central role of DCs in the immune response, they are potential targets for the induction of experimental tolerance. Thus, the generation of immature (tolerogenic) DCs able to capture and present alloantigens to T cells represents an important aim in our efforts to achieve better transplant acceptance., Methods: In this work, we generated immature DCs by using vitamin D(3) (VD3) during the process of DC differentiation., Results: The VD3-DCs showed an immature phenotype characterized by a low expression of major histocompatibility complex antigens of class II, CD86, and CD80 molecules and the secretion of a tolerogenic cytokine pattern. Furthermore, we showed that VD3-DCs phagocytose apoptotic allogeneic cells efficiently without inducing DC maturation or activation. Most important, our experiments demonstrated that mice treated with VD3 produce immature DCs in vivo, and that DCs from VD3-treated mice immunized with allogeneic apoptotic cells maintained their tolerogenic phenotype., Conclusion: Our results show that allogeneic apoptotic cells in combination with VD3 generate DCs with tolerogenic characteristics that could be used to induce tolerance towards alloantigens., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Regulatory T cells play a key role to inhibit effector lymphocytes, avoid, autoimmunity, and restrain allogeneic immunity. Retinoic acid is an important cofactor that stimulates the generation and expansion of regulatory T cells. Naive T cells, coincubated with allogeneic antigen-presenting cells and retinoic acid, in conjunction with transforming growth factor (TGF) β and interleukin (IL) 2, generated allogeneic regulatory T cells de novo. These cells were able to inhibit skin rejection in adoptive transfer experiments. The generation of regulatory T cells ex vivo with retinoic acid, TGF-β, and IL-2 represents a new step toward specific regulation of allogeneic immune responses., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: HLA Matchmaker is a computer algorithm developed to evaluate donor/receptor compatibility comparing sequences of polymorphic aminoacids (eplets) present in human leukocyte antigen (HLA) molecules. The aim of this study was to evaluate the predictive value of HLA Matchmaker for patient and graft survival, graft survival free of rejection, and the presence of anti HLA antibodies., Methods: Using this program, 62 of 173 kidney transplant patients, were retrospectively analyzed. HLA-I loci eplet mismatch value (EMM) was determined and correlated with graft survival, graft survival free of rejection, and the presence of anti HLA-I antibodies. EMM was compared with the traditional HLA antigen mismatch value (MM) in terms of the presence of anti HLA-I antibodies., Results: Graft survival and graft survival free of rejection showed no statistical differences (P-value .975 and .365, respectively) while comparing patients with less or more than 10 HLA-I EMM. Patients with > or =6 HLA-B EMM had an odds ratio (OR) of 5.6 (95% confidence interval [CI], 0.47-66.45) of presenting anti HLA-I antibodies, with a sensitivity of 80% and specificity of 58.3%. For > or =2 HLA-B MM, the OR was 2.58 (95% CI, 0.46-14.5), with a sensitivity of 40% and specificity of 75%., Conclusion: Even though in our study population compatibility by HLA Matchmaker did not correlate with graft survival or rejection-free graft survival, it showed a better sensitivity than traditional HLA antigen matching for the presence of anti HLA-I antibodies. HLA Matchmaker is a promising tool in predicting the appearance of anti-HLA antibodies.

Background: CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) play an essential role in immune tolerance, suppressing responses against self-antigens. Additionally, Treg play an important role in maintaining immunosuppression to alloantigens as well as to other antigens. It is well known that in the gut, a subset of dendritic cells produces retinoic acid (RA), which together with transforming growth factor (TGF-beta) is able to differentiate naïve T cells into Treg. The aim of this study was to establish the role of antigen-presenting cells (APC) in the differentiation of allogeneic Tregs under the effect of RA and TGF-beta., Methods: Splenic CD4(+)CD25(-) naïve T cells from C57BL/6 mice were co-cultured with splenic CD11c-enriched APC from Balb/c mice in the presence of TGF-beta, RA, and interleukin (IL-2). After 6 days of culture, cells were analyzed for the expression of Foxp3 by flow cytometry. Additionally, we investigated the role of B cells and dendritic cells (DCs) and their stimulatory capacity in the generation of Tregs., Results: Our results showed that co-culture of naive T cells with the appropriate level of stimulation by APC in the presence of TGF-beta, RA, and IL-2 provided a new powerful approach to generate allogeneic Treg cells. We demonstrated that although B cells and DCs can generate Tregs by themselves, a mixure of both APC improved their capacity to efficiently generate Tregs. Also, we observed that although the addition of IL-2 to the cultures was not crucial to generate Tregs, it was required to optimize their expansion and cell survival.

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) mediate immunologic self-tolerance and suppress immune responses. In the gut, a subset of dendritic cells is specialized to induce Treg in a transforming growth factor-beta (TGF-beta)- and retinoic acid (RA)-dependent manner. The aim of this study was to establish if RA synergizing with TGF-beta induced antigen specific CD4(+) CD25(high) Foxp3(+) Treg portraying gut homing receptors. Splenic CD4(+)CD25(-) Foxp3(-) naïve T cells from DO11.10 mice were cocultured with splenic CD11c(+) dendritic cells from Balb/c mice in the presence of TGF-beta, RA, and low levels of an antigenic peptide. After 5 days of culture, cells were analyzed for the expression of Foxp3 and the gut homing receptors CCR9 and alpha4beta7. The number of Foxp3(+) T cells generated with TGF-beta and RA was at least 3 times higher than in the cultures with TGF-beta alone and 15 times higher than in controls without exogenous cytokines. Also, supplementation of the cultures with RA induced the expression of the intestinal homing receptors CCR9 and alpha4beta7. Our results showed that coculture of naïve T cells with antigen-presenting cells in the presence of TGF-beta and RA represents a powerful approach to generate Treg with specific homing receptors.

Dendritic cells (DCs) are professional antigen presenting cells with the ability to induce and regulate an immune response. DCs that capture and present antigen under noninflammatory conditions maintain an immature phenotype and acquire tolerogenic properties. These DCs generate regulatory T lymphocytes that potentiate tolerogenic responses. Here we developed a method for the generation of immature murine DCs able to process and present a specific antigen in a tolerogenic context. Immature DCs were prepared from bone marrow precursors after differentiation with granulocyte-macrophage colony-stimulating factor (GM-CSF) in the presence of vitamin D(3) and characterized by their low expression of major histocompatibility complex class (MHC) II and CD86 molecules. Purified phagosomes containing either MHC II molecules or ovalbumin were used to deliver antigens to immature DCs. More than 80% of the DCs captured the phagosomes, while maintaining a low expression of maturation markers and showing basal levels of secretion of activating cytokines such as interleukin (IL)-2 and IL-12. Treatment of the immature DCs with lipopolysaccharides (LPS) increased IL-10 secretion, in agreement with their anti-inflammatory and immune regulatory properties. Cocultures of transgenic OT-II T lymphocytes with the immature DCs carrying OVA-phagosomes succeeded in generating a subpopulation of regulatory T lymphocytes characterized by the expression of CD4, CD25, CD62L, and Foxp3. Taken together, our results suggest that vitamin D(3) generates immune tolerance through the modulation of DC phenotype and could be useful to induce tolerance to allotransplants.