Lymphocyte subsets may discern treatment effects in children and young adults with post-transplant lymphoproliferative disorder

Abstract

To identify potential alternatives to Epstein-Barr virus (EBV)-specific cytotoxic T-cell responses, peripheral lymphocyte subsets (PLS) (CD4+, CD8+, CD3+, CD19+, CD56+) were measured by flow cytometry in children with abdominal transplants (n = 22) and heart transplants (n = 2), with (n = 14) and without (n = 10, group C) post-transplant lymphoproliferative disorder (PTLD). PTLD resolved with reduced immunosuppression and antiviral therapy in eight children (group B). Recalcitrant PTLD was observed in six children (group A). Recalcitrant PTLD followed prior antilymphocyte therapy [monoclonal anti-CD3 antibody (OKT3) and thymoglobin (n = 3) and thymoglobin (n = 1)] for refractory rejection in four of these six children, and resolved after treatment with rituximab (anti-CD20 monoclonal antibody). Ten children without PTLD served as a control group (group C). Between group comparisons showed a numeric increase in CD8 + cells and significantly lower CD4:CD8 ratios in both PTLD groups (A and B) compared with group C. Group A children also demonstrated significant depletion of natural killer (NK) cells, and post-rituximab depletion of B-cells compared with group B (no rituximab treatment). We conclude that NK cell depletion with a reversed CD4:CD8 ratio may represent a persistent immunosuppressed state, which may result from prior antilymphocyte therapy and may predispose to recalcitrant EBV-PTLD. Clinical remission with rituximab is accompanied by B-cell depletion. Serial monitoring of PLS from the time of diagnosis of PTLD will be necessary to confirm these observations.

Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder

“…A higher mean baseline EBV load correlates with heightened risk of PTLD or recurrent PTLD (7,19). Other investigators propose combining EBV DNA measurement with a complementary test, such as EBV-specific T cell enumeration as measured by a peptide tetramer or enzyme-linked immunosorbent spot, EBV serology, reverse transcription-PCR (RT-PCR) targeting EBV transcripts, cytokine gene polymorphism, ATP release, gammopathy by serum protein electrophoresis, microarray-based expression profiles, and CD20 or CD4/CD8/NK cell counts (6,10,17,25,53,107,112,117,123,151,158,166,173,177,192,207,211,213). Some of these tests reflect the immune system's ability to control EBV infection, while other tests reflect general immune function.…”

Flow cytometric lymphocyte subset enumeration: 10 years of external quality assessment in the Benelux countries

“…Furthermore, lymphocyte subset enumeration is an important part of the diagnostic workup in patients with acute leukemia and chronic lymphoproliferative disorders (16). In addition, serial monitoring of lymphocyte subsets allows the evaluation of treatment efficacy in patients with posttransplant lymphoproliferative disorders (17). Another application is to monitor the effectiveness of nutrition supplements in patients receiving peritoneal dialysis (18).…”

“…Each send-out, from spring 1996 to autumn 2005, was chronologically assigned with a unique number (i.e., [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In this way, we analyzed any effect of the EQA program on the variation of results as a function of time.…”

Primary Nonresponse to Anti‐Cd20 Therapy in Gastrointestinal Posttransplant Lymphoproliferative Disorder

“…Although EBV‐negative PTLD might be expected to be less responsive to primary treatment modalities compared with EBV‐related disease, a poor treatment response was observed in association with EBV‐positive PTLD in our patient (19). LeVasseur et al (20) have shown that natural killer cell depletion with a reversed CD4:CD8 ratio might predispose an immunosuppressed patient to recalcitrant PTLD, and they reported successful resolution of PTLD after anti‐CD20 therapy in these cases. Unfortunately, lymphoproliferative disease was highly progressive in our patient, spreading throughout the small intestine with multiple areas of necrosis and perforation despite anti‐CD20 therapy, in contrast with the previous reports of successful results with anti‐CD20 even in recalcitrant PTLD and other forms of non‐Hodgkin lymphoma (20‐22).…”