Graft Versus Host Reactions. Their Natural History, and Applicability as Tools of Research

Abstract Background: Although bronchiolitis obliterans syndrome (BOS) is a well described manifestation of pulmonary involvement by chronic graft-versus-host disease (PcGvHD), additional pulmonary phenotypes of PcGvHD beyond BOS have not been well-characterized. PcGvHD and chronic lung allograft dysfunction (CLAD) in lung transplant recipients share similar pathophysiological mechanisms. We aim to use an adaptation of the International Society for Heart and Lung Transplantation (ISHLT) CLAD Consensus Criteria to describe PcGvHD phenotypes beyond BOS in order to improve the diagnosis and classification of PcGvHD. Methods: We created a new PcGvHD diagnostic and phenotyping criteria based on the 2019 ISHLT CLAD Consensus Criteria (Table 1). Consecutive patients enrolled in the cross-sectional National Institutes of Health (NIH) natural history protocol (NCT00092235) between October 2004 and January 2020 were analyzed for study inclusion. Diagnosis of CLAD-PcGvHD was made when the following criteria were met: 1). New-onset decline of pulmonary function after allogeneic stem cell transplant (AHCT); 2). Forced expiratory volume in one second (FEV1) < 80% predicted with 10% decrease over less than 2 years; 3). Classification into one of the four CLAD-PcGvHD subtypes, [BOS, restrictive lung syndrome (RLS), mixed BOS/RLS (M) and undefined (UD)] was possible; 4). Other causes of pulmonary dysfunction were excluded. Patients without a diagnosis of cGvHD, NIH-performed pulmonary function test (PFT) or thoracic computed tomography (CT) were excluded. Demographic characteristics, AHCT information, GvHD history and treatment information, PFTs, and CT were collected for all study cohort patients. PFTs were analyzed by two independent pulmonologists and thoracic CT studies by an independent cardiothoracic radiologist. The final diagnosis and classification of PcGvHD per the new criteria were made and confirmed by two independent reviewers. Results: Of a total of 447 patients, 21 patients did not have cGvHD, 76 patients did not have NIH-performed PFT and/or CT, leaving 350 patients for the study cohort. The NIH cGvHD global severity score was 3 (severe) in 76% of patients. Evaluation of the study cohort by the new criteria diagnosed CLAD-PcGvHD in a total of 166 (47.4%) patients, including: 12 (3.4%) BOS, 67 (19.1%) RLS, 47 (13.4%) mixed, and 40 (11.4%) UD. In contrast, only 80 (22.9%) patients had documented diagnosis of BOS according to the NIH 2014 cGvHD consensus criteria, i.e., FEV1 < 75% predicted and FEV1/FVC < 0.7. An additional 52 (14.9%) patients had reduced FEV1, but were unable to be classified by the CLAD-PcGvHD criteria (unclassified, UC), therefore did not meet the diagnosis of Pc-GvHD. Compared to patients with normal FEV1 or UC, patients with CLAD-PcGvHD had poorer Karnofsky performance status (KPS) (p=.0001), more commonly received myeloablative conditioning (p=.047) or busulfan (p=.007), had a higher prevalence of liver cGvHD (p=.001), and required more lines of therapy for cGvHD (p=.0001). Between different CLAD-PcGvHD phenotypes, patients with BOS were older at AHCT (p=.005), had higher FEV1 and hemoglobin-adjusted DLCO (p=.0001 and p=.005, respectively), while patients with RLS had higher frequencies of skin or joint/fascia cGvHD (p=0.001 and p=.003, respectively). Median overall survival (OS) after AHCT was 162 months in patients with CLAD-PcGvHD, unreached in UC, and 310 months in patients with normal FEV1 (p=.007); OS was similar between different PcGvHD phenotypes (p=.154). In multivariate analysis, KPS < 80, FEV1 < 40%, adjusted DLCO < 60%, CLAD-PcGvHD, indication for AHCT being lymphoid malignancy, and black race were independent risk factors for OS (Table 2). Conclusion: The CLAD-PcGvHD criteria involves computed tomography in patient evaluation and encompasses a wide spectrum of lung disease post-AHCT. With this criteria, half of the patients in the NIH cGVHD natural history study could be diagnosed and phenotypically classified. The development of CLAD-PcGvHD was an independent risk factor for post-transplant survival. The proposed criteria could become a valuable all-encompassing clinical tool in studying post-AHCT lung disease and facilitate the study across solid organ and hematopoietic stem cell transplantation. Figure 1 Figure 1. Disclosures Pavletic: Center for Cancer Research: Research Funding; National Cancer Institute: Research Funding; National Institutes of Health: Research Funding; Celgene: Research Funding; Actelion: Research Funding; Eli Lilly: Research Funding; Pharmacyclics: Research Funding; Kadmon: Research Funding.

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Elevated BAFF Is Correlated with Inflammatory Processes in Chronic Graft Versus Host Disease and Supports Increases in Transitional B Cells

Blood ◽

10.1182/blood.v112.11.465.465 ◽

2008 ◽

Vol 112 (11) ◽

pp. 465-465 ◽

Cited By ~ 1

Author(s):

Frances T. Hakim ◽

Najibah Rehman ◽

John Dickinson ◽

Sivasubramanian Baskar ◽

Christoph M. Rader ◽

...

Keyword(s):

B Cells ◽

Natural History ◽

B Cell ◽

Graft Versus Host Disease ◽

Negative Selection ◽

Cell Populations ◽

Graft Versus Host ◽

Post Transplant ◽

Transitional B Cells ◽

Inflammatory Processes

Abstract B Cell Activating Factor of the TNF Family (BAFF) plays a critical role in the survival, activation and function of B cells. Elevated levels of BAFF in plasma, however, have been reported in systemic autoimmune disorders and in chronic graft versus host disease (CGVHD). We similarly observed elevated plasma BAFF levels in 98 patients in an ongoing NCI CGVHD natural history protocol, with a median of 2653 pg/ml (range 92 to 14907), as compared to 556 pg/ml (range 75 to 1834) in 18 normal donors. Furthermore, in a subset of 40 patients in which severity of cutaneous CGVHD could be assessed by the presence of marked erythema or sclerosis, BAFF levels correlated with total percentage body surface area involvement (p<0.02). We then explored the factors that might contribute to elevated BAFF levels. In recipients recovering from either autologous or allogeneic transplant (without GVHD) we observed the highest BAFF levels at day 0 (median of 10534 and 12240 pg/ml respectively), when B cells were severely depleted. As B cell populations recovered to normal levels post transplant, plasma BAFF concentrations declined (Spearman r = −.80 and r = −.60, respectively), consistent with homeostatic cytokine-consumption dynamics. Despite comparably high levels of BAFF (median of 11342 pg/ml) at transplant day 0 in 16 patients who later developed CGHVD, BAFF levels in the cross-sectional, natural history patient population were only moderately correlated with the degree of post transplant B cell recovery (r = −.46). Since inflammatory triggers can induce elevated BAFF production, we assessed plasma levels of cytokines indicative of an inflammatory process. In 98 patients, the plasma levels of IP-10 and sTNFRII correlated positively with BAFF levels (r = +.579 and r = +.396, respectively), consistent with active inflammatory processes in those CGVHD patients with elevated BAFF levels. In a multi-step regression model, the levels of circulating B cells, plasma IP-10 and sTNFRII combined to strongly predict BAFF levels (R =.704). These findings suggest that both homeostatic recovery of B cell populations consuming BAFF and inflammatory cytokine cascades initiated by donor-anti-host reactivity combine to regulate BAFF levels post transplant. Although a broad range of autoimmune symptoms have been described in CGVHD, the mechanisms by which donor-anti-host reactivity can result in autoimmunity remains poorly understood. In murine models, elevated BAFF levels have been associated with increased survival of the transitional B cell population, altering the normal processes of B cell negative selection, and resulting in failure to eliminate auto-reactive B cells. We therefore assessed whether elevated BAFF levels were associated with increased frequencies of transitional CD21− T1 B cells in CGVHD patients. In 79 CGVHD patients, the median percentage of CD19+CD21− transitional B cells was 6.13% (range 1% to 39.4%) as compared to 2.24% (range 0.66% to 7.44%) in 40 healthy adult donors. Furthermore, the frequency of CD21− transitional B cells was significantly higher in those patients with higher BAFF levels (p<.002). Finally, the expression (mean fluorescent intensity (MFI)) of the BAFF receptor (BAFF-R) was reduced in patients with CGVHD compared with normal donors, consistent with down-regulation upon BAFF consumption; among CGVHD patients, receptor MFI was inversely correlated with BAFF levels (Spearman r = −.44). Elevated BAFF levels in CGVHD therefore may both reflect the inflammatory processes initiated by donor-anti-host reactivity and contribute to the later generation of pathologic autoantibodies by dysregulation of B cell negative selection.

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How is the moral stance related to the intentional stance and group thinking?

Behavioral and Brain Sciences ◽

10.1017/s0140525x19002413 ◽

2020 ◽

Vol 43 ◽

Author(s):

Hannes Rakoczy

Keyword(s):

Natural History ◽

Social Cognitive ◽

Intentional Stance ◽

Cognitive Capacities ◽

Shared Intentionality ◽

History Of ◽

Group Thinking ◽

Moral Stance

Abstract The natural history of our moral stance told here in this commentary reveals the close nexus of morality and basic social-cognitive capacities. Big mysteries about morality thus transform into smaller and more manageable ones. Here, I raise questions regarding the conceptual, ontogenetic, and evolutionary relations of the moral stance to the intentional and group stances and to shared intentionality.

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On the assembly and structural modulation of lens fiber junctions

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100110805 ◽

1984 ◽

Vol 42 ◽

pp. 110-113

Author(s):

E.L. Benedetti ◽

I. Dunia ◽

Do Ngoc Lien ◽

O. Vallon ◽

D. Louvard ◽

...

Keyword(s):

Molecular Weight ◽

Natural History ◽

Intercellular Junctions ◽

Eye Lens ◽

Membrane Domains ◽

Functional Polymorphism ◽

Lens Fiber ◽

The Past ◽

Structural Modulation ◽

Biochemical Difference

In the eye lens emerging molecular and structural patterns apparently cohabit with the remnants of the past. The lens in a rather puzzling fashion sums up its own natural history and even transient steps of the differentiation are memorized. A prototype of this situation is well outlined by the study of the lenticular intercellular junctions. These membrane domains exhibit structural, biochemical and perhaps functional polymorphism reflecting throughout life the multiple steps of the differentiation of the epithelium into fibers and of the ageing process of the lenticular cells.The most striking biochemical difference between the membrane derived from the epithelium and from the fibers respectively, concerns the presence of the 26,000 molecular weight polypeptide (MP26) in the latter membranes.

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