Acute allograft rejection: cellular and humoral processes

Tereza Martinu, Elizabeth N Pavlisko, Dong-Feng Chen, Scott M Palmer, Tereza Martinu, Elizabeth N Pavlisko, Dong-Feng Chen, Scott M Palmer

Abstract

Acute cellular rejection affects greater than one-third of lung transplant recipients. Alloreactive T-lymphocytes constitute the basis of lung allograft rejection. Recent evidence supports a more complex immune response to the allograft. Interaction between recipient genetics, immunosuppression therapies, and allograft environmental exposures likely contribute to high rejection rates after lung transplantation. A greater understanding of the heterogeneous mechanisms of lung rejection is critical to developing effective therapies that target the precise pathophysiology of the disease and ultimately improve long-term lung transplant outcomes.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
Venn diagram representing the relationship between acute cellular rejection (grade A and grade B) and humoral rejection manifest by presence of anti-HLA antibodies or histologic findings.
Fig. 2
Fig. 2
Examples of acute lung allograft rejection pathology. (A–D) Grade A acute cellular rejection; arrows indicate vessel lumina. (A) Grade A1 acute rejection with rare perivascular lymphocytes, H&E. (B) Grade A2 acute rejection with a prominent perivascular mononuclear infiltrate, H&E. (C) Grade A3 acute rejection with extensive perivascular infiltrate extending into interstitial spaces, H&E. (D) Grade A4 acute rejection with a diffuse mononuclear infiltrate with lung injury, including fibrinous exudate (arrowhead), H&E. (E) Grade B1R (low-grade) lymphocytic bronchiolitis with small numbers of bronchiolar mononuclear cells, H&E. (F) Grade B2R (high-grade) lymphocytic bronchiolitis with dense bronchiolar mononuclear infiltrate and epithelial involvement, H&E. (G) Neutrophilic capillaritis consistent with humoral rejection (arrowheads indicate neutrophils), H&E, with (H) associated immunofluorescence on frozen lung tissue, demonstrating ring-shaped profiles of C4d staining in alveolar septal capillaries, Immunofluorescent staining. All images are at 200× magnification.
Fig. 3
Fig. 3
Flow cytometric antibody screening for measurement of panel reactive antibody (PRA). FlowPRA beads are coated with purified HLA antigens. After incubation with patient serum and subsequent staining with FITC-labeled antihuman immunoglobulin (Ig)G, FlowPRA beads were analyzed on a flow cytometer. Beads with antibody binding have greater fluorescence intensity as represented by the rightward channel shift compared with the negative control. A percentage value of PRA is calculated based on the area of peak shifted. This patient demonstrated a PRA of 95% for HLA class 1 and a PRA of 94% for HLA class 2. The multiple peaks in the positive flow histogram are due to different bead populations emitting fluorescence of different intensity. The negative control was generated using uncoated beads. FITC, fluorescein isothiocyanate.
Fig. 4
Fig. 4
Standard Luminex single antigen (SA) bead assay results for detection of specific anti-HLA antibodies. SA bead numbers are listed in red on the x-axis. Each SA bead is coated with multiple copies of a single recombinant HLA antigen. The mean fluorescence intensity (MFI), which represents the strength of antibody binding to the beads, is plotted on the y-axis: the color of the bar represents the score of the antibody reactivity strength. The specific HLA antigens tested are listed in the gray chart below the graph. For this patient, positive antibody reactivities were assigned to the 6 beads DQB1*03:01/DQA1*05:03, DQB1*02:01/DQA1*05:01, DQB1*03:01/DQA1*05:05, DQB1*03:01/DQA1*06:01, DQB1*02:01/DQA1*04:01, and DQB1*04:01/DQA1*04:01 based on the cutoff established in the laboratory. Therefore, the patient has specific antibodies against HLA DQA 1 chains encoded by DQA1 alleles DQA1*05:03, DQA1*05:01, DQA1*05:05, DQA1*06:01, and DQA1*04:01. The presence of antibodies against DQB1 chains encoded by alleles DQB1*03:01, DQB1*02:01, and DQB1*04:01 can be excluded based on the negative reactivities with other beads, which also carry the DQB1 chains/antigens encoded by these alleles.

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