Vascular leak syndrome and serositis as an unusual manifestation of chronic graft-versus-host disease in nonmyeloablative transplants.
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Capillary Leak Syndrome↗
Biomedical subjects
D C Roy
Publications and source records attributed to D C Roy.
Maintaining high autopsy rates in a Canadian blood and marrow transplant program: preserving a diagnostic and research tool.
Autopsy series have revealed patterns of injury in graft-versus-host disease and provided insight into infectious and toxic complications following hematopoietic stem cell transplantation (HSCT). Overall autopsy rates have declined significantly in recent decades including specialized services such as neonatal medicine and cardiac care. However, rates of post-mortem exams at HSCT centers have not been specifically documented. We reviewed hospital records between 1992 and 2002 to determine overall autopsy rates at our hospital and within the HSCT program. Although the overall autopsy rate declined steadily from 24% in 1992 to 9% in 2002, rates of post-mortem exams in the HSCT program remained relatively stable at 32% (24-46%). Autopsy rates were not significantly different for recipients of allogeneic vs autologous transplants and no clear difference was observed for the proportion of autopsies requested on weekdays compared with weekends. Autopsies confirmed major clinical diagnoses and/or suspected causes of death in 45 of 61 autopsies (74%) and yielded major or minor disagreements in clinical diagnosis in 10 cases (16%) and seven cases (11%), respectively. The preservation of high rates of autopsy within our HSCT program demonstrates that specialized programs are able to maintain elevated rates of post-mortem examinations despite overall declining rates.
Autopsy↗
Elimination of alloreactive T cells using photodynamic therapy.
GvHD, the most important cause of morbidity and mortality after allogeneic stem cell transplantation, depends primarily on the ability of a donor T-cell subset to react to immunogenic host Ag. Recently developed culture conditions and treatment strategies may bring us closer to the selective elimination of such alloreactive T cells, often considered the holy grail of transplantation. Among the various therapeutic modalities, photodynamic therapy (PDT) offers a biological and global approach to the eradication of unwanted allo-activated T cells by combining mitochondrial targeting, P-glycoprotein inhibition and reactive oxygen species production. Indeed, the high potency of PDT against malignant cells has been harnessed to exert selective and extensive elimination of alloreactive T-cell subsets mediating GvHD, while preserving resting T cells with the ability to reconstitute the immune system for GvL activity and prevent or suppress viruses and fungi. The present paper reviews the basis of the PDT strategy, and the methodology employed. In vitro and in vivo studies that formed the proof of principle as a basis for human studies to investigate the clinical potential of PDT in the context of GvHD will be presented together with insights into future clinical applications of this versatile treatment platform.
Graft vs Host Disease↗
Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease.
Adoptive transfer of T cells reactive to minor histocompatibility antigens has the unmatched ability to eradicate malignant hematopoietic cells. Unfortunately, its use is hampered by the associated graft-versus-host disease. The critical issue of a possible dissociation of the antileukemic effect and graft-versus-host disease by targeting specific minor histocompatibility antigens remains unresolved because of the unknown nature and number of minor histocompatibility antigens necessary or sufficient to elicit anti-leukemic activity and graft-versus-host disease. We found that injection of T lymphocytes primed against a single major histocompatibility complex class I-restricted immunodominant minor histocompatibility antigen (B6dom1) caused no graft-versus-host disease but produced a curative anti-leukemic response. Avoidance of graft-versus-host disease required that no other host-reactive T cells be co-injected with T cells primed with B6dom1. Here we show that effective and non-toxic immunotherapy of hematologic malignancies can be achieved by targeting a single immunodominant minor histocompatibility antigen.
Adoptive Transfer↗
Allogeneic transplantation for multiple myeloma: further evidence for a GVHD-associated graft-versus-myeloma effect.
We report a series of 37 consecutive patients with multiple myeloma (MM) who received an allograft between 1990 and 2000 at our institution. Median age was 47 years, and nearly 70% of patients were Durie-Salmon stage III. A median of five cycles of chemotherapy were given before transplant, with a median interval between diagnosis and transplant of 9.3 months. We report a nonrelapse mortality rate of 22% with a median follow-up period of 40 months, whereas complete remission (CR) rate at 12 months is estimated at 57%. Treatment failure rate and overall survival at 40 months are estimated at 52% and 32%, respectively. The number of chemotherapy cycles prior to allotransplantation achieved borderline statistical significance as a poor prognosis factor for overall survival (P = 0.05), while the presence of chronic graft-versus-host disease (cGVHD) was significantly correlated with CR achievement (P = 0.036). Our study confirms that early allografting in MM can yield toxicity rates significantly lower than those associated with historical cohorts, and supports the hypothesis that cumulative chemotoxicity has a negative influence on mortality and survival rates. More importantly, our study clearly demonstrates an association between cGVHD and CR and brings further evidence in favor of a graft-versus-myeloma effect.
Adult↗
Relapse after bone marrow transplantation: evidence for distinct immunological mechanisms between adult and paediatric populations.
Donor lymphocyte infusions are particularly effective for remission induction in malignant cells in patients who relapse after allogeneic progenitor cell transplantation (PCT) and who remain sensitive to the administration of unprimed donor T and/or natural killer (NK) cells present in donor lymphocyte infusions. To determine whether relapse after unmanipulated PCT could be ascribed to donor T and/or NK cell loss or tolerization, we evaluated the chimeric status of 81 patients with haematological malignancies who were receiving allogeneic unmanipulated PCT. The incidence of mixed chimaerism (MC) in unfractionated mononuclear leucocyte samples decreased rapidly after transplant, and was not detectable 4 months after PCT, even in patients who subsequently relapsed. The chimeric status of immune effector cell subsets was then evaluated in 15 patients at the time of relapse. All adults demonstrated complete donor haematopoiesis (CDH) for all cell lineages, whereas T- and NK-cell MC was only found in patients younger than age 13 years (P = 0.004). MC was not found in T nor NK cells of a control group consisting of age-matched paediatric patients in remission after allogeneic PCT. Thus, in adults, T and NK cell MC disappears early after unmanipulated allogeneic PCT and is absent at the time of relapse. However, the identification of donor T and NK cell loss in the paediatric relapsed but not remission patients suggests a distinct mechanism of relapse.
Adolescent↗
The in vivo fate of APCs displaying minor H antigen and/or MHC differences is regulated by CTLs specific for immunodominant class I-associated epitopes.
The goal of this work was to evaluate the fate of APCs following interactions with T cells in unprimed mice with a normal T cell repertoire. We elaborated a model in which male adherent peritoneal mononuclear cells were injected into the foreleg footpads of naive female recipients mismatched for either minor or major histocompatibility Ags. At various times after injection, APC numbers in the draining (axillary and brachial) lymph nodes were assessed using a Ube1y gene-specific PCR assay. Our experimental model was designed so that the number of APCs expressing the priming epitope was similar to what is observed under real life conditions. Thus, early after injection, the frequency of afferent lymph-derived APCs expressing the priming epitope was in the range of 101-102/106 lymph node cells. We found that APCs presenting some, but not all, nonself epitopes were killed rapidly after entrance into the lymph nodes. Rapid elimination of APCs occurred following interactions with MHC class I-restricted, but not class II-restricted, T cells and was observed when APCs presented an immunodominant (B6dom1/H7a), but not a nondominant (HY), epitope. Killing of APCs was mediated partly, but not exclusively, by perforin-dependent process. We propose that killing of APCs by CTLs specific for immunodominant MHC class I-restricted epitopes may be instrumental in regulating the intensity, duration, and diversity of T cell responses.
Animals↗
Massive activation-induced cell death of alloreactive T cells with apoptosis of bystander postthymic T cells prevents immune reconstitution in mice with graft-versus-host disease.
After hematopoietic stem cell transplantation, the persistence and expansion of grafted mature postthymic T cells allow both transfer of donor immunologic memory and generation of a diverse T repertoire. This thymic-independent process, which is particularly important in humans, because most transplant recipients present severe thymus atrophy, is impaired by graft-versus-host disease (GVHD). The goal of this study was to decipher how GVHD influences the fate of grafted postthymic T cells. Two major findings emerged. First, we found that, after a brisk proliferation phase, alloreactive antihost T cells underwent a massive activation-induced cell death (AICD). For both CD4(+) and CD8(+) T cells, the Fas pathway was found to play a major role in this AICD: alloreactive T cells upregulated Fas and FasL, and AICD of antihost T cells was much decreased in the case of lpr (Fas-deficient) donors. Second, whereas non-host-reactive donor T cells neither upregulated Fas nor suffered apoptosis when transplanted alone, they showed increased membrane Fas expression and apoptosis when coinjected with host-reactive T cells. We conclude that GVHD-associated AICD of antihost T cells coupled with bystander lysis of grafted non-host-reactive T cells abrogate immune reconstitution by donor-derived postthymic T lymphocytes. Furthermore, we speculate that massive lymphoid apoptosis observed in the acute phase of GVHD might be responsible for the occurrence of autoimmunity in the chronic phase of GVHD.
Animals↗
The effect of graft-versus-host disease on T cell production and homeostasis.
The aim of this work was to decipher how graft-versus-host disease (GVHD) affects T cell production and homeostasis. In GVHD+ mice, thymic output was decreased fourfold relative to normal mice, but was sufficient to maintain a T cell repertoire with normal diversity in terms of Vbeta usage. Lymphoid hypoplasia in GVHD+ mice was caused mainly by a lessened expansion of the peripheral postthymic T cell compartment. In 5-bromo-2'-deoxyuridine pulse-chase experiments, resident T cells in the spleen of GVHD+ mice showed a normal turnover rate (proliferation and half-life). When transferred into thymectomized GVHD- secondary hosts, T cells from GVHD+ mice expanded normally. In contrast, normal T cells failed to expand when injected into GVHD+ mice. Thus, the reduced size of the postthymic compartment in GVHD+ mice was not due to an intrinsic lymphocyte defect, but to an extrinsic microenvironment abnormality. We suggest that this extrinsic anomaly is consistent with a reduced number of functional peripheral T cell niches. Therefore, our results show that GVHD-associated T cell hypoplasia is largely caused by a perturbed homeostasis of the peripheral compartment. Furthermore, they suggest that damage to the microenvironment of secondary lymphoid organs may represent an heretofore unrecognized cause of acquired T cell hypoplasia.
Animals↗
Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.
Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.
Amino Acid Sequence↗
Lymphoma cell burden in progenitor cell grafts measured by competitive polymerase chain reaction: less than one log difference between bone marrow and peripheral blood sources.
A controversy persists in autologous transplantation as to which source of progenitor cells, bone marrow (BM) or peripheral blood (PB), contains the lowest number of contaminating lymphoma cells, and how mobilization procedures affect these numbers. To accurately measure the number of non-Hodgkin's lymphoma (NHL) cells harboring the bcl-2/immunoglobulin H (IgH) rearrangement in progenitor cell grafts, we developed a nested quantitative competitive polymerase chain reaction assay (QC-PCR). DNA from lymph nodes of four patients with NHL were cloned into the pSK(+) vectors to generate four internal controls (ICs) (two with major breakpoint region [MBR] and two with minor cluster region [mcr] rearrangements). The kinetics of amplification of ICs paralleled those of bcl-2/IgH rearranged genomic DNA. When used in a QC-PCR assay, these ICs were accurate at a 0.2-log level and provided reproducible results, as shown by low intrarun and interrun variability. An excellent correlation between predicted and observed lymphoma cell content (r = .99) was observed over a range of at least 5 logs of rearranged cells. This approach was used to measure involvement by NHL cells at the time of progenitor cell harvest in 37 autologous transplant patients. The number of bcl-2/IgH rearranged cells in BM, PB, and mobilized PB (mPB) was found to vary from 1 to 1.1 x 10(5) per million cells. The number of lymphoma cells present in BM was significantly higher than in PB (P = .0001), with a median difference in lymphoma cell content between BM and PB of 0.48 log of cells (range, -0.7 to 5 logs). In contrast, we found no difference in the concentration of bcl-2/IgH rearranged cells present in BM versus PB progenitor cells mobilized with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) (mPB) (P = .57). In conclusion, the QC-PCR assay described in this study could measure accurately and reproducibly the number of bcl-2/IgH rearranged cells among normal cells. Differences in levels of contamination by lymphoma cells between BM and PB were of less than one log (10-fold), and no differences in lymphoma cell concentrations were observed between BM and mobilized PB. As more cells are usually infused with mPB than with BM grafts, mPB progenitor cell grafts may actually be associated with higher levels of contamination by lymphoma cells. Furthermore, this QC-PCR assay should provide an important tool to assess the prognostic impact of lymphoma cell burden both in progenitor cell grafts and in vivo.
Adult↗
Immunodominant minor histocompatibility antigens: the major ones.
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Animals↗
Quantitative assessment of hematopoietic chimerism after allogeneic bone marrow transplantation has predictive value for the occurrence of irreversible graft failure and graft-vs.-host disease.
Primary graft failure, secondary to either host-vs.-graft reaction or delayed engraftment, and graft-vs.-host disease (GVHD) are among the most difficult clinical problems to manage in the field of allogeneic bone marrow transplantation (BMT). Early diagnosis of both conditions would greatly improve their outcome. Using fluorescence in situ hybridization (FISH) with an X- and Y-probe mixture, we sequentially monitored chimerism of neutrophils and lymphoid cells from day 1 to 100 in 28 consecutive recipients of sex-mismatched unmanipulated bone marrow grafts. The objective was to quantitatively assess the evolution of chimerism during this crucial time interval and to determine whether chimerism patterns would be predictive of engraftment and GVHD. In recipients with primary graft failure (n=7), the presence of donor-type neutrophils and NK cells as well as the predominance of donor-type T cells distinguished patients who responded to G-CSF (n=5) from nonresponders (n=2). Furthermore, the clearance of host CD3+CD56- cells during days 5-10 posttransplantation was significantly hastened in patients who subsequently developed acute (delta=80%) or chronic (delta=81%) GVHD compared with patients without GVHD (delta=17%). Thus, our data suggest that molecular monitoring of the fate of host/donor hematopoietic cells in the early posttransplantation period could be useful in differentiating patients with delayed engraftment from those with irreversible rejection and in predicting the occurrence of GVHD as soon as day 10. This investigational approach may provide an appropriate basis on which to select adequate treatment for primary graft failure and high-risk candidates that could benefit from novel preemptive therapies for GVHD.
Bone Marrow Transplantation↗
Conjugation of blocked ricin to an anti-CD19 monoclonal antibody increases antibody-induced cell calcium mobilization and CD19 internalization.
CD19 (B4) is a signal transduction molecule restricted to the B-cell lineage and the target of the immunotoxin anti-B4-blocked ricin (anti-B4-bR), which is composed of the monoclonal antibody (MoAb) anti-B4 and the modified plant toxin blocked ricin. To explore the influence of conjugation of blocked ricin to anti-B4 on functional activation of CD19, we investigated the effects of anti-B4-bR, and that of unconjugated anti-B4, on intracellular calcium mobilization and ligand/receptor internalization. The data showed that anti-B4-bR was more potent than anti-B4 in triggering cell calcium mobilization. Two other immunotoxins that bind to the B-cell surface, anti-CD20-bR and anti-CD38-bR, were devoid of the calcium increasing effect of anti-B4-bR. Furthermore, anti-B4 conjugated to ricin A-chain was also without effect in Namalwa cells, indicating that the ricin B-chain component was required for anti-B4-bR effect. Anti-B4-bR-induced calcium mobilization was inhibited in the presence of lactose, yet the calcium response induced by cross-linking anti-B4-bR with a second step antibody was not affected. The extent of CD19 modulation induced by anti-B4-bR was higher than that induced by anti-B4, and lactose dampened the effect of the immunotoxin down to that of the MoAb. Moreover, the number of internalized immunotoxin molecules was higher than that of unconjugated MoAb. Although a mechanism involving dimerization of the immunotoxin cannot be excluded, our findings suggest that the residual binding activity of the blocked ricin B-chain to cell surface molecules plays an important role in the greater calcium fluxes and greater internalization rate of anti-B4-bR, and is of functional significance in the mechanism of intoxication of cells by the immunotoxin.
ADP-ribosyl Cyclase↗
Thymic and extrathymic differentiation and expansion of T lymphocytes following bone marrow transplantation in irradiated recipients.
Thymic function is severely impaired in most marrow transplant recipients. To evaluate the impact of thymic hypoplasia on T cell reconstitution following marrow transplantation, we compared the phenotype and function of T lymphocytes in thymectomized recipients with those of euthymic hosts. Irradiated C57BL/6 mice (Thy1.2+, Ly5.1+) received 10(7) T cell-depleted B6.Ly5.2 bone marrow cells (Thy1.2+, Ly5.2+), with or without 3 x 10(5) B6.PL lymph node cells (Thy1.1+, Ly5.1+) as a source of T lymphocytes. Multiparameter flow cytometry analysis showed that in euthymic mice (group 1), T cell reconstitution was carried out by donor hematopoietic stem cells that differentiated in the host's thymus, whereas the production of chimeric T cells in athymic recipients depended on the presence or absence of T cells in the graft. When T lymphocytes were present in the graft (group 2), their progeny constituted the vast majority of splenic T cells on day 100 posttransplant. When the graft did not contain T lymphocytes (group 3), T cell reconstitution resulted from extrathymic maturation of donor hematopoietic progenitors; T cells differentiating along this pathway expressed lower levels of T cell receptor and a large proportion of the CD8+ subset expressed CD8alpha alpha homodimers. The T cell receptor Vbeta profile of all chimeras was similar to that of normal C57BL/6 mice. Compared with T cells found in euthymic recipients, those in mice from groups 2 and 3 were less abundant (particularly with respect to the CD4+ subset), displayed the CD44/CD45 phenotype of activated memory cells, and expressed high levels of IL-2 receptor beta chain. These results show that both the presence or absence of the thymus and the composition of the grafted inoculum determine the source and extent of posttransplant T cell reconstitution. Because they determine the nature of the differentiation pathway taken during T cell development in the host, these two factors can exert a critical influence on the appearance of graft vs. host disease and the level of host immunocompetence.
Animals↗
Elimination of neuroblastoma and small-cell lung cancer cells with an anti-neural cell adhesion molecule immunotoxin.
BACKGROUND: The development of immunotoxins has been hampered by difficulties, particularly in solid tumors, of finding appropriate target antigens and of linking sufficiently potent toxins. PURPOSE: We evaluated the tissue specificity of an immunotoxin, N901-blocked ricin (N901-bR), and assessed its potential for eliminating neural cell adhesion molecule (NCAM)-positive tumor cells in conditions appropriate for in vitro purging, prior to autologous stem cell transplantation, and its potential for myelosuppression. N901-bR consists of a monoclonal antibody (MAb), N901, directed against CD56, an antigen of the family of NCAMs, covalently linked to blocked ricin as the cytotoxic effector moiety. METHODS: The tissue specificity of the N901 MAb and the N901-bR immunotoxin was tested against a wide array of human tumor tissues and normal human tissues by immunohistochemical staining. The cytotoxic activity of N901-bR was tested against both small-cell lung cancer (SCLC) cells and neuroblastoma cells, either alone or among normal bone marrow mononuclear cells, and the efficacy of this treatment to specifically eliminate these cells was evaluated in a limiting dilution assay. In addition, normal bone marrow mononuclear cells were incubated with N901-bR, and the toxic effects of the immunotoxin on normal hematopoietic progenitors was evaluated. RESULTS: N901 and N901-bR exhibited specificity for several neoplasms of neuroectodermal origin, including SCLC and neuroblastoma. Staining of normal tissues was essentially limited to various neuroendocrine cells, cardiac muscle cells, and cells in peripheral nerve tissue. We observed a time- and dose-dependent elimination of tumor cells in vitro, with three logs (i.e., > 99.9%) of malignant cells being killed following only 5 hours of exposure to 10 nM N901-bR. Unconjugated N901 MAb specifically blocked the elimination of NCAM-positive cells by N901-bR, whereas neither an isotype-matched control MAb nor galactose (the ligand of native ricin) had any effect on the activity of the immunotoxin, confirming the specificity of its cytotoxic activity. Importantly, N901-bR used under optimal conditions for in vitro tumor cell depletion was not toxic to hematopoietic precursors. CONCLUSIONS: N901-bR has the properties required to target CD56, an antigen present not only on cells from a large number of cancers of neuroendocrine origin, but also on some important normal tissues. In addition, treatment with this immunotoxin results in the highly effective and specific elimination of neuroblastoma and SCLC cells and does not affect normal hematopoietic progenitors. IMPLICATIONS: N901-bR may have clinical utility for purging of neuroblastoma cells and SCLC cells before autologous stem cell transplantation. Further toxicology studies are warranted to assess the potential of N901-bR for in vivo administration.
Antibodies, Monoclonal↗
Identification of an immunodominant mouse minor histocompatibility antigen (MiHA). T cell response to a single dominant MiHA causes graft-versus-host disease.
T cell responses to non-MHC antigens are targeted to a restricted number of immunodominant minor histocompatibility antigens whose identity remains elusive. Here we report isolation and sequencing of a novel immunodominant minor histocompatibility antigen presented by H-2Db on the surface of C57BL/6 mouse cells. This nonapeptide (AAPDNRETF) shows strong biologic activity in cytotoxic T lymphocyte sensitization assays at concentrations as low as 10 pM. C3H.SW mice primed with AAPDNRETF in incomplete Freund's adjuvant generated a potent anti-C57BL/6 T cell-mediated cytotoxic activity, and T lymphocytes from AAPDNRETF-primed mice caused graft-versus-host disease when transplanted in irradiated C57BL/6 recipients. These results (a) provide molecular characterization of a mouse dominant minor histocompatibility antigen, (b) identify this peptide as a potential target of graft-versus-host disease and, (c) more importantly, demonstrate that a single dominant minor antigen can cause graft-versus-host disease. These findings open new avenues for the prevention of graft-versus-host disease and should further our understanding of the mechanisms of immunodominance in T cell responses to minor histocompatibility antigens.
Amino Acid Sequence↗
Endometrial T, B, and NK cells in patients with recurrent spontaneous abortion. Altered profile and pregnancy outcome.
Several lines of evidence indicate that immunologic effectors, particularly suppressor T cells and NK cells, may play a role in the pathogenesis of idiopathic repetitive abortions. To investigate the involvement of these immune cell populations, we determined the immunophenotypic characteristics of endometrial leukocytes from nonpregnant recurrent aborters. Habitual aborters with a negative investigation underwent an endometrial biopsy during their secretory phase and were followed prospectively to assess clinical outcome. Endometrial leukocytes were evaluated by two-color flow cytometric analysis. The percentage of endometrial CD8+ T lymphocytes was significantly decreased in recurrent aborters, and their CD4:CD8 ratio was increased. In contrast, the proportion of B lymphocytes (CD20+) was strikingly increased in these patients' endometria. The proportion of NK cells was identical in recurrent aborters and normal controls, but the CD16-CD56 bright NK cell subset, which is predominant in normal decidua and endometrium, was significantly decreased in favor of an important contingent of CD16+CD56 dim NK cells in all habitual aborters. Repetitive aborters who had normal CD8+ and CD20+ cell numbers and a normal CD4:CD8 ratio subsequently underwent successful pregnancies, while patients with continuing abortions presented lymphoid populations observed in the habitual aborters group. In conclusion, endometrial lymphocytes of recurrent spontaneous aborters harbor a distinct immunophenotypic profile that antedates implantation and suggests that endometrial immunologic conditions are intrinsically altered in recurrent aborters. Also, the prognostic impact of CD8 and CD20 expression supports their predominant role in the development of fetal tolerance. Finally, a role for NK cells in the abortion process is suggested by their altered subsets in all repetitive aborters.
Abortion, Habitual↗