Effect Of Major Histocompatibility Complex Research Articles

Generation of Monkey Induced Pluripotent Stem Cell-Derived Cartilage Lacking Major Histocompatibility Complex Class I Molecules on the Cell Surface.

Due to the poor capacity for articular cartilage to regenerate, its damage tends to result in progressively degenerating conditions such as osteoarthritis. To repair the damage, the transplantation of allogeneic human induced pluripotent stem cell (iPSC)-derived cartilage is being considered. However, although allogeneic cartilage transplantation is effective, immunological reactions can occur. One hypothetical solution is to delete the expression of major histocompatibility complex (MHC) class I molecules to reduce the immunological reactions. For this purpose, we deleted the β2 microglobulin (B2M) gene in a cynomolgus monkey (crab-eating monkey [Macaca fascicularis]) iPS cells (cyiPSCs) to obtain B2M−/− cyiPSCs using the CRISPR/Cas9 system. Western blot analysis confirmed B2M−/− cyiPSCs lacked B2M protein, which is necessary for MHC class I molecules to be transported to and expressed on the cell surface by forming multimers with B2M. Flow cytometry analysis revealed no B2M−/− cyiPSCs expressed MHC class I molecules on their surface. The transplantation of B2M−/− cyiPSCs in immunodeficient mice resulted in teratoma that contained cartilage, indicating that the lack of MHC class I molecules on the cell surface affects neither the pluripotency nor the chondrogenic differentiation capacity of cyiPSCs. By modifying the chondrogenic differentiation protocol for human iPSCs, we succeeded at differentiating B2M+/+ and B2M−/− cyiPSCs toward chondrocytes followed by cartilage formation in vitro, as indicated by histological analysis showing that B2M+/+ and B2M−/− cyiPSC-derived cartilage were positively stained with safranin O and expressed type II collagen. Flow cytometry analysis confirmed that MHC class I molecules were not expressed on the cell surface of B2M−/− chondrocytes isolated from B2M−/− cyiPSC-derived cartilage. An in vitro mixed lymphocyte reaction assay showed that neither B2M+/+ nor B2M−/− cyiPSC-derived cartilage cells stimulated the proliferation of allogeneic peripheral blood mononuclear cells. On the contrary, osteochondral defects in monkey knee joints that received allogeneic transplantations of cyiPSC-derived cartilage showed an accumulation of leukocytes with more natural killer cells around B2M−/− cyiPSC-derived cartilage than B2M+/+ cartilage, suggesting complex mechanisms in the immune reaction of allogeneic cartilage transplanted in osteochondral defects in vivo.Impact statementThe transplantation of allogeneic induced pluripotent stem cell (iPSC)-derived cartilage is expected to treat articular cartilage damage, although the effects of major histocompatibility complex (MHC) in immunological reactions have not been well studied. We succeeded at creating B2M−/− cynomolgus monkey (cy)iPSCs and cyiPSC-derived cartilage that lack MHC class I molecules on the cell surface. B2M−/− cyiPSC-derived cartilage cells did not stimulate the proliferation of allogeneic peripheral blood mononuclear cells in vitro. On the contrary, the transplantation of B2M−/− cyiPSC-derived cartilage into osteochondral defects in monkey knee joints resulted in survival of transplants and accumulation of leukocytes, including natural killer cells, suggesting complex mechanisms for the immune reaction.

MHC class I diversity predicts non-random mating in Chinese alligators (Alligator sinensis)

The major histocompatibility complex (MHC) has several important roles in kin recognition, pathogen resistance and mate selection. Research in fish, birds and mammals has suggested that individuals optimise MHC diversity, and therefore offspring fitness, when choosing mates. In reptiles, however, it is unclear whether female mate choice is based on genome-wide genetic characteristics such as microsatellite DNA loci, particular functional-trait loci (e.g., MHC) or both, and MHC's effects on mate choice remain relatively understudied. Herein, we used 13 microsatellite loci and two MHC class I loci to investigate female mate choice of Chinese alligators (Alligator sinensis) in the semi-natural condition. We also determined correlations between the MHC genotype of breeding males and male reproductive success. We found that MHC-heterozygous males harbour a greater reproductive success, which probably is the reason that these males are more preferred by the females than MHC-homozygous males. Furthermore, the MHC class I amino-acid distance and functional distance of true mating pairs were higher compared with those of randomly sampled pairs. Analysis of microsatellites revealed that, despite mate choice, females did not completely avoid inbreeding. These findings are the first evidence of MHC-associated mate choice in Chinese alligators, suggesting that females may adopt different mating strategies after assessing the MHC characteristics of potential mates.

Accumulating evidence suggests that men do not find body odours of human leucocyte antigen-dissimilar women more attractive.

In our recent study published in Proceedings of the Royal Society B [1], we investigated the effects of major histocompatibility complex (MHC; or human leucocyte antigen system, HLA in humans) on men's preferences for women's body odours. Using rigorous methods, we found no evidence that men find body odours of HLA-dissimilar women more attractive than odours of HLA-similar women. In his comment, Wedekind [2] claims that our conclusions were premature, because he found (using our data) a stronger negative relationship between pleasantness and intensity for HLA-dissimilar odours than for similar ones. Although this is an interesting finding, it cannot be considered as a support for HLA-related mate preferences. Wedekind's comment is rather misleading, for various reasons. First, empirical evidence for HLA-mediated body odour preferences in humans is not nearly as clear as the author would like to assume. In the 20 years since Wedekind et al .'s seminal work [3], various studies examining HLA-influences on body odour preferences in humans have been published and the reported findings are mixed. In fact, a recent meta-analysis by Winternitz, Abbate [4] revealed that over all studies with human and non-human primates, results on MHC-mediated body odour preferences are inconsistent and non-significant. It is important to note that Wedekind [2] misinterprets the meta-analysis by Winternitz et al . [4]: These authors found preferences for MHC heterozygosity but not for …

Culture-expanded allogenic adipose tissue-derived stem cells attenuate cartilage degeneration in an experimental rat osteoarthritis model.

Mesenchymal stem cell (MSC)-based cell therapy is a promising avenue for osteoarthritis (OA) treatment. In the present study, we evaluated the efficacy of intra-articular injections of culture-expanded allogenic adipose tissue-derived stem cells (ADSCs) for the treatment of anterior cruciate ligament transection (ACLT) induced rat OA model. The paracrine effects of major histocompatibility complex (MHC)-unmatched ADSCs on chondrocytes were investigated in vitro. Rats were divided into an OA group that underwent ACLT surgery and a sham-operated group that did not undergo ACLT surgery. Four weeks after surgery mild OA was induced in the OA group. Subsequently, the OA rats were randomly divided into ADSC and control groups. A single dose of 1 × 106 ADSCs suspended in 60 μL phosphate-buffered saline (PBS) was intra-articularly injected into the rats of the ADSC group. The control group received only 60 μL PBS. OA progression was evaluated macroscopically and histologically at 8 and 12 weeks after surgery. ADSC treatment did not cause any adverse local or systemic reactions. The degeneration of articular cartilage was significantly weaker in the ADSC group compared to that in the control group at both 8 and 12 weeks. Chondrocytes were co-cultured with MHC-unmatched ADSCs in trans-wells to assess the paracrine effects of ADSCs on chondrocytes. Co-culture with ADSCs counteracted the IL-1β-induced mRNA upregulation of the extracellular matrix-degrading enzymes MMP-3 and MMP-13 and the pro-inflammatory cytokines TNF-α and IL-6 in chondrocytes. Importantly, ADSCs increased the expression of the anti-inflammatory cytokine IL-10 in chondrocytes. The results of this study indicated that the intra-articular injection of culture-expanded allogenic ADSCs attenuated cartilage degeneration in an experimental rat OA model without inducing any adverse reactions. MHC-unmatched ADSCs protected chondrocytes from inflammatory factor-induced damage. The paracrine effects of ADSCs on OA chondrocytes are at least part of the mechanism by which ADSCs exert their therapeutic activity.

Facial Nerve Recovery in KbDb and C1q Knockout Mice: A Role for Histocompatibility Complex 1.

Background:Understanding the mechanisms in nerve damage can lead to better outcomes for neuronal rehabilitation. The purpose of our study was to assess the effect of major histocompatibility complex I deficiency and inhibition of the classical complement pathway (C1q) on functional recovery and cell survival in the facial motor nucleus (FMN) after crush injury in adult and juvenile mice.Methods:A prospective blinded analysis of functional recovery and cell survival in the FMN after a unilateral facial nerve crush injury in juvenile and adult mice was undertaken between wild-type, C1q knockout (C1q−/−), and KbDb knockout (KbDb−/−) groups. Whisker function was quantified to assess functional recovery. Neuron counts were performed to determine neuron survival in the FMN after recovery.Results:After facial nerve injury, all adult wild-type mice fully recovered. Juvenile mice recovered incompletely corresponding to a greater neuron loss in the FMN of juveniles compared with adults. The C1q−/− juvenile and adult groups did not differ from wild type. The KbDb−/− adults demonstrated 50% recovery of whisker movement and decreased cell survival in FMN. The KbDb−/− juvenile group did not demonstrate any difference from control group.Conclusion:Histocompatibility complex I plays a role for neuroprotection and enhanced facial nerve recovery in adult mice. Inhibition of the classical complement pathway alone does not affect functional recovery or neuronal survival. The alternative and mannose binding pathways pose alternative means for activating the final components of the pathway that may lead to acute nerve damage.

Effect of MHC Haplotype on Immune Response upon Experimental SHIVSF162P4cy Infection of Mauritian Cynomolgus Macaques

Little is known about the effects of Major Histocompatibility Complex (MHC) haplotypes on immunity to primate lentiviruses involving both acquired and innate immune responses. We present statistical evidence of the influence of MHC polymorphism on antiviral immunity of Mauritian cynomolgus macaques (MCM) following simian/human immunodeficiency virus SHIVSF162P4cy infection, involving the production of pro- and anti-inflammatory cytokines and α-defensins, which may modulate acquired immune responses. During the acute phase of infection, IL-10 correlated positively with viral load and negatively with CD4+T cell counts. Furthermore, α-defensins production was directly correlated with plasma viral RNA, particularly at peak of viral load. When the effects of the MHC were analyzed, a significant association between lower anti-Env binding and neutralizing antibody levels with class IB M4 haplotype and with class IA, IB M4 haplotype, respectively, was observed in the post-acute phase. Lower antibody responses may have resulted into a poor control of infection thus explaining the previously reported lower CD4 T cell counts in these monkeys. Class II M3 haplotype displayed significantly lower acute and post-acute IL-10 levels. In addition, significantly lower levels of α-defensins were detected in class IA M3 haplotype monkeys than in non-M3 macaques, in the post-acute phase of infection. These data indicate that the MHC could contribute to the delicate balance of pro-inflammatory mechanisms, particularly with regard to the association between IL-10 and α-defensins in lentivirus infection. Our results show that host genetic background, virological and immunological parameters should be considered for the design and interpretation of HIV-1 vaccine efficacy studies.

In Vivo Development of Murine NK Cells Early after Congeneic BMT: Effects of MHC Molecules, and the Administration of hIL-15.

Natural Killer (NK) cells are lymphocytes of the innate immune system that are able to kill a variety of tumors and pathogen-infected cells without prior sensitization. NK cells are the first lymphoid cells to repopulate following bone marrow transplantation (BMT). The present study shows that murine NK cells developing in vivo after BMT are phenotypically and functionally distinguishable from mature adult NK cells. Using a congeneic BMT mouse model (CD45.1/H-2b → C57BL/6, CD45.2/H-2b) we demonstrated here that donor derived BM-NK progenitors (CD122+NK1.1-CD3-)were present in the BM and periphery (spleen), at day 14 after BMT, and developed into NK cells expressing high levels of CD122, NKG2D, CD94, DX5 and CD43. However, surface expression of Ly49 inhibitory receptors was altered with Ly49C/I being under-expressed (9.8 %± 3.2 %), and Ly49G2 being highly expressed (62 %± 3.1 %) when compared to NK cells from non-transplanted adult mice (Ly49C/I, 43.1 %± 7.6 % and Ly49G2, 44.3 %± 13.5 %). At 28 days after BMT, there was a normalization with regard to Ly49 phenotype. The developing NK cells manifested functional deficits compared to non-transplanted adult NK, even when stimulated in vitro with Interleukin (IL)-2, as evidenced by decreased interferongamma (IFN-g) production and cytolytic activity. In order to examine the effects of major histocompatibility complex (MHC) molecules on NK development independently of allelic variation of Ly49s, we performed syngeneic BMT using B10D2 mice (H-2d). We observed the same pattern of Ly49s expression during NK development demonstrating that the acquisition of these receptors early after BMT is not determined by the MHC haplotype. Because IL-15 plays a crucial role in NK cell development, we administrated human (h) IL-15, via hydrodynamic injection of the respective gene, at day 11 after BMT, to accelerate NK maturation. This method resulted in a high but transient production of hIL-15 (736 ± 41 pg/ml) in the serum for up to 2 weeks. A subsequent but temporary increase in the numbers of donor derived NK cells (3 fold) occurred within 72 hours, in both BM and periphery, following hIL-15 gene delivery. Despite these augmenting effects, the developing NK cells still exhibited poor functionality compared to non-transplanted adult mice. These studies describe the possibility of NK development in the spleen, and indicate that normal surface expression of Ly49C/I and Ly49G2 early after BMT is time dependent, but MHC independent. Moreover, administration of hIL-15 is not sufficient to induce NK functional maturation early after BMT despite increased NK numbers.

Contrasting genetic effects of major histocompatibility complex on ischemic peripheral nerve and spinal cord injury in female rats

We have recently shown that the major histocompatibility complex (MHC) exerts a regulatory influence on the development of neuropathic pain-like behaviors after partial sciatic nerve injury in male rats. In the present study, we assessed the role of the MHC in peripheral nerve injury-induced pain as well as central pain following spinal cord injury in female rats using the following inbred strains: Dark Agouti (DA; RT1(av1)), Piebald Virol Glaxo (PVG; RT1(c)) and in the MHC-congenic strain PVG-RT1(av1). In line with our previous observation in male rats, PVG-RT1(c) displayed more severe allodynia compared to the strains carrying the RT1(av1) haplotype (PVG-RT1(av1) and DA-RT1(av1)) following sciatic nerve injury in female rats. However, the MHC did not seem to impact the development of allodynia following spinal cord injury since the two congenic strains PVG-RT1(c) and PVG-RT1(av) did not differ after spinal cord injury. Interestingly, the DA-RT1(av1) strain displayed significantly more severe allodynia than both PVG strains and this difference was not explained by the extent of spinal cord injury. These results suggest that there are differences in the genetic mechanisms for neuropathic pain development following peripheral or central nervous system injury, both in regarding to the role of the MHC complex as well as non-MHC genes.

Major histocompatibility complex effect on cellulitis among different chicken lines

The chicken major histocompatibility complex (MHC) has been implicated in conferring resistance/susceptibility to several bacterial, parasitic, and viral diseases. Investigators have shown that the chicken MHC plays a major role in determining the outcome of a Marek's disease infection, in that standard B 13 is susceptible to the virus while B 21 confers resistance to the virus. Previous work with a broiler line has shown that B 21 is susceptible to an Escherichia coli -induced cellulitis infection and that B 13 conferred resistance to the infection. For this experiment, a broiler and a Leghorn chicken line shown to contain standard B 13 and B 21 were examined in a challenge model for cellulitis. The birds were challenged with a cellulitis-causing E. coli isolate. Homozygous B 21 had the highest incidence of cellulitis development compared with either homozygous B 13 or the heterozygous B 13 / B 21 for both the broiler and Leghorn lines. Additionally, cellulitis lesion severity was measured in both lines and shown to be independent of MHC type.

Posttransplant lymphoproliferative disorder after liver transplantation in miniature swine.

Posttransplant lymphoproliferative disorder (PTLD) is a well-known, life-threatening complication of immunosuppressive therapy, occurring in both adult and pediatric transplant recipients. To study the effect of major histocompatibility complex on tolerance induction to primarily vascularized liver allograft, a semi-identical miniature swine model was developed to mimic the clinical situation of parent-into-infant liver transplantation. Long-term acceptance of semi-identical liver allograft was obtained by a transient course of FK506. In a subgroup of six animals, three developed a lethal PTLD. These animals were studied by histology and immunohistochemistry and the anti-donor cellular immune response was assessed. In addition, the possible viral origin of the proliferative process was evoked. Histology and immunohistochemistry revealed an abnormal B-cell proliferation in many organs of swine suffering from PTLD. Evidence of human Epstein-Barr virus, cytomegalovirus, and adenovirus was not evidenced, but a porcine virus responsible for a respiratory and reproductive syndrome (PRRS) was identified in the lymphoid tissue of these animals. In mixed lymphocyte reaction, a significant antiself immune response confirmed an infection by a virus. This is the first report suggesting that PRRS virus might provoke PTLD in immunosuppressed miniature swine after orthotopic liver transplantation. Whether PTLD could be induced by injection of the PRRS virus in immunosuppressed animals, a pig model of PTLD might be developed and would represent an interesting preclinical model for testing anti-PTLD therapies.

Immunological aspects of fresh and cryopreserved aortic valve transplantation in rats

Background. The influence of immune activation on valve allograft degeneration remains unclear. We studied the combined effect of major histocompatibility complex (MHC)-incompatibility and cryopreservation on valve performance, histomorphology, and tissue antigenicity in rats.Methods. Fresh or cryopreserved allogeneic aortic valves from WAG (RT1u) rats were transplanted to DA (RT1a) recipients and syngenic transplants served as controls. After 7 or 21 days, valves were examined for competence and morphology. Immune reactivity of the recipient was measured by concanavalin A (conA) stimulation and analysis of donor-reactive Helper T-lymphocyte frequencies (HTLf) in peripheral blood and spleen.Results. Syngenic grafts demonstrated normal competence and structure. Allografts lost their competence over time caused by destruction of the leaflets combined with cellular infiltration in the vascular wall. Cryopreservation induces early loss of competence and retrovalvular thrombosis. Cryopreserved allografts were also heavily infiltrated. ConA stimulation indices and HTLf were higher in allogeneic recipients compared to syngenic recipients (p < 0.03). Cryopreserved allografts elicited a lower immune response compared with fresh allografts (p < 0.03).Conclusions. Aortic valve allografts are able to induce a donor-reactive immune response that is related to early graft destruction and incompetence. Cryopreservation appears to diminish but not eliminate the antigenicity of the allograft.

Effects of major histocompatibility complex matching on graft survival in allogeneic rat limb transplantation.

Differences in the major histocompatibility complex (MHC) between recipients and donors present a problem because of immunologic responses in graft rejection. The purpose of this study is to clarify the efficacy of MHC matching against acute graft rejection of allogeneic limb transplants in rats. Right hindlimb transplantations were performed using various MHC-mismatched pairs of inbred rats. The rats were classified into 5 groups according to the differences in subregions of the RT1 (rat MHC) between the recipient and the donor: group 1, RT1-A,B,D barrier (the differences of RT1-A,B,D subregions); group 2, RT1-A barrier; group 3, RT1-B,D barrier; group 4, RT1-B barrier; and group 5, RT1-D barrier. The mean survival time significantly decreased in group 1 and increased in group 4. The results suggest that MHC matching clearly improves survival of transplanted limbs. Specifically, both RT1-A and D matching is the most effective compatibility in prolonging survival time of allogeneic limb transplants in rats.

Genetic line and major histocompatibility complex effects on primary and secondary antibody responses to T-dependent and T-independent antigens

The effects of MHC and nonMHC (background) genetics on the kinetics of primary and secondary antibody responses to T-cell-dependent (SRBC) and T-cell-independent [Brucella abortus (BA)] antigens were investigated. Eight genetic groups were represented, with four homozygous MHC haplotypes [B1-IrGATlow (IrGAT = immune response to GAT locus); B1-IrGAThigh; B19-Ir-GATlow; B19-IrGAThigh] on two genetic backgrounds, the S1 and G lines. Birds were injected simultaneously with BA and SRBC at 4 and 7 wk of age, and blood samples were taken weekly from 4 to 10 wk of age for measurement of total agglutinating serum antibody levels. A quadratic equation and its first derivative were computed for each bird to approximate individual curve parameters: y max, the maximum titer; t max, the time required to achieve y max; and c coefficient, the rate of decline in the titer. Curve parameters of birds from different lines were analyzed separately by using the General Linear Model procedure. A second analysis that included line effect evaluated the nonMHC gene effects and their interactions with erythrocyte antigen B locus (Ea-B) or IrGAT. In the S1 line, there was an interaction (P < 0.05) between MHC haplotypes and sex for primary response to BA. In contrast, there were no significant main effects nor interactions in the G line background for primary and secondary responses to BA and SRBC. There was an effect (P < 0.05) of line background on y max for primary BA and for secondary SRBC responses. A positive correlation (P < 0.05) was found between the c coefficients of BA and SRBC secondary responses, suggesting that the rate of decline in the secondary response is similar between these T-dependent and T-independent responses. The overall results of this study indicate complex interactions between specific MHC alleles and the nonMHC background of the lines in which they are studied.

Incomplete T-Cell Immune Reconstitution in Two Major Histocompatibility Complex Class II–Deficiency/Bare Lymphocyte Syndrome Patients After HLA-Identical Sibling Bone Marrow Transplantation

To study the effects of major histocompatibility complex (MHC) class II expression on T-cell development, we have investigated T-cell immune reconstitution in two MHC class II-deficiency patients after allogeneic bone marrow transplantation (allo-BMT). Our study showed that the induction of MHC class II antigen expression on BM graft-derived T cells in these allo-BMT recipients was hampered upon T-cell activation. This reduction was most striking in the CD8(+) T-cell subset. Furthermore, the peripheral T-cell receptor (TCR) repertoire in these graft-derived MHC class II-expressing CD4(+) and in the CD8(+) T-cell fractions was found to be restricted on the basis of TCR complementarity determining region 3 (CDR3) size profiles. Interestingly, the T-cell immune response to tetanus toxoid (TT) was found to be comparable to that of the donor. However, when comparing recipient-derived TT-specific T cells with donor-derived T cells, differences were observed in TCR gene segment usage and in the hydropathicity index of the CDR3 regions. Together, these results reveal the impact of an environment lacking endogenous MHC class II on the development of the T-cell immune repertoire after allo-BMT.

Resistance to Toxoplasma gondii in mice infected as neonates or exposed in utero.

Mice were exposed to the protozoan parasite Toxoplasma gondii in utero or were infected as neonates in order to identify and characterize resistance mechanisms that function protectively during the first weeks after birth. About one-half of the mice born of mothers fed T. gondii cysts at 11 days of gestation survived to weaning age or beyond. No effect of major histocompatibility complex (MHC) haplotype on early survival was observed in a group of backcross progeny; however, long-term survival was strongly dependent on MHC haplotype. The ability of mice infected as neonates to survive until weaning was found to depend on gamma interferon and on Thy-1+ cells but not on CD4+ or CD8+ cells. Mice that survived to maturity after infection as neonates were slightly more resistant to challenge with virulent T. gondii parasites than were sham-infected controls but were less resistant than were mice infected as adults. Together the results indicate the following. (i) Mice congenitally infected with T. gondii have a gamma interferon-dependent mechanism of early resistance that involves Thy-1+ cells but not CD4+ or CD8+ cells. (ii) This mechanism is not under MHC-linked genetic control. (iii) Mice that exhibit long-term survival after congenital infection acquire a modest degree of protection against reinfection with virulent organisms. (iv) The extent of long-term survival of congenitally infected neonates, like that in mice infected as adults, is influenced by MHC genes, presumably via MHC-restricted CD4+ and/or CD8+ cells.

Decreased adhesion to endothelial cells and matrix proteins of H-2Kb gene transfected tumour cells.

Transfection of murine metastatic B78H1 cells (derived from B16 melanoma) with a syngeneic H-2Kb gene was used to study the effect of Major Histocompatibility Complex (MHC) gene products on tumour cell adhesion to endothelial cells and matrix proteins and the involvement in the metastatic process. H-2Kb-expressing transfectants showed a reduced adhesion to endothelial surfaces of different origin (four murine endotheliomas and human umbilical vein endothelial cells) when compared to parental B78H1 cells and to controls transfected with pSV2neo alone. On the average a 50-70% reduction in adhesion to endothelial cells was observed among H-2Kb transfectants. H-2Kb transfectants had a reduced expression of the alpha 4 integrin subunit, moreover the adhesion of Neo-transfected clones to endothelial cells was reduced to the levels of H-2Kb transfectants by antibodies directed against the beta 1 subunit and the endothelial VCAM-1 molecule, thus suggesting an impairment of the VLA-4/VCAM-1 interaction in H-2Kb transfectants. Adhesion to extracellular matrix components was also strongly decreased: in general the adhesion of H-2Kb cells showed a 50-75% inhibition with respect to Neo or parental controls. The highest difference was observed in adhesion to vitronectin and laminin, the lowest in adhesion to fibronectin. Reduction in adhesive properties of H-2Kb-expressing transfectants could be involved in the reduced metastatic ability, evaluated by means of intravenous injection of cells: H-2Kb transfectants yielded less than ten lung colonies, while all controls produced more than 100. Our data indicate that expression of a single class I MHC gene can significantly alter the metastatic phenotype of MHC-negative tumour cells and this could be related to a general alteration of tumour cell adhesive interactions.

Effects of major histocompatibility complex on antibody response in F1 and F2 crosses of chicken lines

Effects of major histocompatibility complex on antibody response in F₁ and F₂ crosses of chicken lines

Effects of major histocompatibility complex on antibody response in F1 and F2 crosses of chicken lines

Effects of major histocompatibility complex on antibody response in F1 and F2 crosses of chicken lines

Effect of major histocompatibility complex on clonal proliferation of CD 5&lt;sup&gt;+&lt;/sup&gt;B cells.

自己免疫疾患の発症が主要組織適合遺伝子複合体 (MHC) と相関を示し, また自己免疫疾患患者家系にリンパ系悪性腫瘍が好発することが知られている. さらに最近, ある種の自己抗体を産生することからCD5+B細胞が注目されているが, このCD5+B細胞はBリンパ系悪性腫瘍, 殊にB細胞性慢性リンパ性白血病 (B-CLL) の発症母地とも考えられている. これらのことから自己免疫疾患とBリンパ系悪性腫瘍の発症機構に何らかの関連性があることが示唆される. 今回, われわれは全身性エリテマトーデス (SLE) のモデルマウスであり, しかも脾臓中にCD5+B細胞数の増加の認められるNew Zealandマウス系を用いて, この両疾患の関連性を検討した. New ZealandマウスのSLE病態の発症は, マウスのMHCであるH-2のハプロタイプに強く規定されており, H-2d/H-2zのヘテロ接合性が必須であることをわれわれは今までに見い出している. 本研究ではH-2-congenicマウスを用いて, 脾臓CD5+B細胞数がH-2ハプロタイプによって影響をうけるか否かを検討した. その結果H-2z/H-2zハプロタイプを持つマウス系において, H-2d/H-2dあるいはH-2d/H-2zハプロタイプのマウスよりも, 脾臓CD5+B細胞比率が非常に高いことが明らかとなった. しかもこれらの増殖CD5+B細胞は最終的にはoligoclonalになり, 中にはmonoclonalなB-CLL到る例も認められた. 一方, 腹腔におけるCD5+B細胞比率は脾臓の場合とは異なり, いずれのH-2ハプロタイプのマウス系においても違いは認められず, 脾臓と腹腔におけるCD5+B細胞増殖は異なる機序で制禦され, また異なるcloneが増殖していることが判明した. 以上の結果から, New Zealandマウスにみられる脾臓CD5+B細胞のクローナル増殖および, B-CLLの発症にはNZW 系のもつH-2z複合体に隣接して存在する遺伝子座がホモの状態で存在することが必要であることが示された. このことは自己免疫疾患とB-CLLの発症が異なってはいるが, いずれも関連性のあるMHCによって規定されていることを示しており, ヒトにおいて両疾患の発症が, 家族性に発症することの原因を解明する一つの糸口となると考えられる.

Effects of major histocompatibility complex on autoimmune disease of H-2-congenic New Zealand Mice

Autoimmune-prone NZB mice mainly produce IgM-class anti-DNA antibodies and mild SLE develops later in life. The F1 hybrid of NZB and non-autoimmune NZW mice (NZB/W F1 mice) develop a more fulminant SLE, associated with decreases in IgM class, and, in turn, increases in IgG class anti-DNA antibodies. To elucidate the role of the H-2 complex in this mode of anti-DNA antibody production, we established and studied H-2-congenic New Zealand mice, i.e. NZB, NZW, and NZB/W F1 mice with either the homozygous H-2z/H-2z or H-2d/H-2d haplotype or the heterozygous H-2d/H-2z haplotype. The data showed that: (i) although the non-H-2-linked NZB gene(s) seems to determine the IgM anti-DNA antibody production in NZB mice, the effect of this gene is fully expressed only in the case of the H-2d/H-2d homozygous state. (ii) The production of IgG anti-DNA antibodies observed in NZB/W F1 hybrid mice is restricted to the H-2d/H-2z heterozygosity. (iii) Because both NZB and NZW mice with the H-2d/H-2z haplotype produce a lower titer of IgG anti-DNA antibodies than do the NZB/W F1 mice, other complementary non-H-2-linked genetic elements from both NZB and NZW parents are required. The development of lupus nephritis correlated well with that of anti-DNA antibodies. Thus, H-2d/H-2z heterozygosity is a necessary but not sufficient condition for the development of autoimmunity in NZB/W F1 mice.(ABSTRACT TRUNCATED AT 250 WORDS)