Molecules In Transplantation Research Articles

HLA molecules in transplantation, autoimmunity and infection control: A comic book adventure.

HLA molecules in transplantation, autoimmunity and infection control: A comic book adventure.

An update on potentials and promises of T cell co‐signaling molecules in transplantation

The promising outcomes of immune-checkpoint based immunotherapies in cancer have provided a proportional perspective ahead of exploiting similar approaches in allotransplantation. Belatacept (CTLA-4-Ig) is an example of costimulation blockers successfully exploited in renal transplantation. Due to the wide range of regulatory molecules characterized in the past decades, some of these molecules might be candidates as immunomodulators in the case of tolerance induction in transplantation. Although there are numerous attempts on the apprehension of the effects of co-signaling molecules on immune response, the necessity for a better understanding is evident. By increasing the knowledge on the biology of co-signaling pathways, some pitfalls are recognized and improved approaches are proposed. The blockage of CD80/CD28 axis is an instance of evolution toward more efficacy. It is now evident that anti-CD28 antibodies are more effective than CD80 blockers in animal models of transplantation. Other co-signaling axes such as PD-1/PD-L1, CD40/CD154, 2B4/CD48, and others discussed in the present review are examples of critical immunomodulatory molecules in allogeneic transplantation. We review here the outcomes of recent experiences with co-signaling molecules in preclinical studies of solid organ transplantation.

Immunobiology of HLA Class-Ib Molecules in Transplantation

Immunobiology of HLA Class-Ib Molecules in Transplantation

Allele and haplotype frequencies of HLA‐DPA1 and ‐DPB1 in the population of Guadeloupe

Genetic polymorphism of human leukocyte antigen (HLA)-DPA1 and -DPB1 loci was studied in 154 unrelated individuals from Guadeloupe, an archipelago of five islands located in the Carribean Sea. Thirty different DPB1 and eight different DPA1 alleles were observed with a heterozygosity index of 0.87 and 0.78, respectively. This high degree of heterozygosity corresponds with those found in African populations. The DPB1* 01:01:01 allele was most frequent (0.260), followed by 02:01:02 (0.143) and 04:01:01 (0.127). The DPA1 alleles 01:03 (0.380), 02:01 (0.302), 02:02 (0.175) and 03:01 (0.123) were identified in >35 individuals each, whereas 01:04, 01:05 and 04:01 were present only once. Haplotype estimations revealed the presence of 39 different haplotypes, with DPB1*01:01:01-DPA1*02:02 and DPB1*02:01:02-DPA1*01:03 as the most frequent (0.143 and 0.140, respectively). A striking difference was observed in DPB1/DPA1 associations between DPB1*04:02 and *105:01, that have identical exon 2 sequences. DPB1*04:02 was exclusively associated with DPA1*01:03, whereas DPB1*105:01 was present with DPA1*03:01, *03:02 or *04:01. This implies that the DP molecules are actually different, and this difference is relevant to consider in studies on the function of HLA-DP molecules in transplantation. Overall, HLA-DPA1 and DPB1 allele frequencies and haplotypes of the population of Guadeloupe were most similar to African populations, with characteristic alleles and haplotypes that bespeaks the admixture with other ethnicities.

Targeting co-stimulatory pathways: transplantation and autoimmunity.

The myriad of co-stimulatory signals expressed, or induced, upon T-cell activation suggests that these signalling pathways shape the character and magnitude of the resulting autoreactive or alloreactive T-cell responses during autoimmunity or transplantation, respectively. Reducing pathological T-cell responses by targeting T-cell co-stimulatory pathways has met with therapeutic success in many instances, but challenges remain. In this Review, we discuss the T-cell co-stimulatory molecules that are known to have critical roles during T-cell activation, expansion, and differentiation. We also outline the functional importance of T-cell co-stimulatory molecules in transplantation, tolerance and autoimmunity, and we describe how therapeutic blockade of these pathways might be harnessed to manipulate the immune response to prevent or attenuate pathological immune responses. Ultimately, understanding the interplay between individual co-stimulatory and co-inhibitory pathways engaged during T-cell activation and differentiation will lead to rational and targeted therapeutic interventions to manipulate T-cell responses and improve clinical outcomes.

Clinical Significance of HLA-E*0103 Homozygosity on Survival After Allogeneic Hematopoietic Stem-Cell Transplantation

Hematopoietic stem-cell transplantation is a well-established treatment in various hematologic malignancies, but the outcome depends on disease relapse, infections, and the development and severity of acute and chronic graft-versus-host disease. Some evidence has revealed an important role for the nonclassical major histocompatibility complex class I molecules in transplantation, most notably human leukocyte antigen (HLA)-E. This study evaluates the impact of HLA-E alleles on transplantation outcome after HLA-matched allogeneic HSCT. We genotyped DNA for HLA-E polymorphism from 83 recipients and their respective donors by real-time polymerase chain reaction after melting curve analysis and compared the results with clinical outcome. HLA-E*0103 homozygous patients showed a higher probability of overall survival (P=0.003) and disease-free survival (P=0.001) in a univariate model. Cox regression analysis confirmed HLA-E*0103, 0103 (P=0.006; relative risk 1.12; 95% confidence interval 0.31-1.94) and early stage of disease (P=0.005; relative risk 1.16; 95% confidence interval 0.45-1.86) as independent factors improving overall survival. Moreover, homozygosity for HLA-E*0103 was associated with a significant decreased incidence of transplant-related mortality (P=0.01). We found an association between HLA-E*0103 homozygosity and the significant reduction of transplant-related mortality in related and unrelated HSCT. The risk of posttransplant complications was significantly reduced when the donor possesses the HLA-E*0103, 0103 genotype, and this was translated in a better overall survival.

The role of positive costimulatory molecules in transplantation and tolerance

The manipulation of costimulatory pathways holds tremendous potential for treating immunologically mediated diseases. In this article, we review the role of molecules that deliver a positive second signal that, together with an antigen-specific signal from the T-cell receptor, is necessary to promote complete T-cell activation, differentiation and development of effector function. Numerous positive costimulatory molecules have been identified: CD28/B7, induced costimulatory/induced costimulatory ligand, CD40/CD154, OX40/OX40L, CD27/CD70, 4-1BB/4-1BBL, LIGHT/herpes virus entry mediator, glucosyltransferase R and T-cell immunoglobulin mucin molecules. Many of these have been only recently discovered and remain incompletely studied. Recent work has demonstrated that some costimulatory molecules bind ligands expressed by nonprofessional activated protein C, some modulate regulatory T cells and some sustain rather than initiate immune responses. Emerging data suggest that the costimulatory pathways are redundant and that the various costimulatory molecules affect different T-cell populations and act at different times during the course of the immune response. These observations suggest that the therapeutic exploitation of strategies targeting costimulatory molecules will require carefully timed interventions directed against multiple pathways.

The allogeneic response and tumor immunity

The strong allogeneic response to donor MHC molecules in transplantation and the weak response to tumor antigens represent two important and divergent but potentially interactive immune responses. A patient's response to allogeneic MHC molecules might promote an effective T-cell response to self MHC-restricted tumor peptides and the possibilities for this are discussed here. These allogeneic responses might successfully be harnessed to promote the immune eradication of metastatic cancer.

Cell-mediated graft rejection observed in two lines of human histocompatibility leukocyte antigen class I transgenic mice.

Human histocompatibility leukocyte antigen (HLA) class I molecules are essential for graft rejection. However, to determine the specific role of these molecules in clinical situations is difficult. We investigated the applicability of HLA class I transgenic mice (C3H.B35 and C3H.B51) for elucidation of the role of HLA class I molecules. Skin or heart grafts were transplanted. Cytotoxic T cells (CTL) of C3H.B51 against C3H.B35 were generated and their cytotoxicity against various transfectant cell lines was determined. C3H.B35 skin and heart grafted to C3H.B51 were rejected within 17 and 28 days, respectively. Cytotoxic T cells generated from C3H.B51 showed cytotoxicity against a HLA-B*3501-transfectant cell line that did not express H-2 molecule, which indicates that these cytotoxic T cells recognize HLA-B35 molecules directly without H-2 restriction. Our results suggest that C3H.B51 recognize C3H.B35 grafts as allo-MHC class I-incompatible grafts, and these mice are valuable to elucidate the role of HLA class I molecules in transplantation.

Restriction fragment analysis of the HLA Class II region: Application to tissue transplantation

Southern blotting and hybridization with locus specific probes is a reliable method for the determination of HLA Class II specificities and in conjunction with several other techniques is providing valuable information on the nature of Class II polymorphisms in man. In terms of the identification of Class II specificities in transplantation however, the advanced nature of DR serology means that DR beta restriction fragment analysis is probably limited only to those situations where serological methods have been unsuccessful. Whether DQ and DP incompatibilities can evoke rejection responses in vivo remains to be fully ascertained although our preliminary data suggest that DQ mismatches probably have little effect upon graft outcome. Restriction fragment analysis is particularly attractive in that it enables reliable retrospective studies to be performed in conjunction with prolonged clinical follow up, and the technique will clearly continue to contribute significantly to our understanding of the importance of these molecules in transplantation.

Peptide map comparisons of epidermal and spleen H-2 molecules

Peptide map comparisons of molecules encoded in the mouse H-2 complex isolated from epidermal cell preparations have been carried out. We previously showed that the Ia molecules from both the I-A and I-E subregions are synthesized by nonlymphoid bone-marrow-derived cells, probably Langerhans cells. The K and D or transplantation molecules are synthesized by both "true" epidermal cells and nonlymphoid bone-marrow-derived cells. The tryptic maps generated by separating tryptic peptides by high pressure liquid chromatography (HPLC) of epidermal H-2 molecules are identical to their spleen-cell counterparts. The biological significance of this finding is discussed.

Chemical Characterization of Products of the H-2 Complex

The following topics are discussed: general features of the H-2 complex; isolation and preliminary chemical characterization of transplantation molecules; amino acid sequence analysis of the K and D molecules; genetic and evolutionary implications of N-terminal amino acid sequences of transplantation antigens; general properties of the I-region-associated (IA) alloantigens; and chemical characterization of Ia molecules. (HLW)