Mogamulizumab-induced photosensitivity in patients with mycosis fungoides and other T-cell neoplasms.

BACKGROUND: Mogamulizumab (Mog) is a defucosylated, therapeutic monoclonal antibody, targeting CCR4 and was first approved in Japan for the treatment of adult T-cell leukaemia/lymphoma (ATLL), followed by cutaneous T-cell lymphoma and peripheral T-cell lymphoma. OBJECTIVE: To retrospectively investigate development of photosensitivity in patients with mycosis fungoides and other T-cell neoplasms after treatment with Mog. METHODS: We treated seven cutaneous lymphoma patients with Mog. Upon combination treatment with narrow-band UVB, we noticed that four patients developed photosensitivity dermatitis following Mog therapy, including two cases of mycosis fungoides, one case of adult T-cell leukaemia/lymphoma and one case of EB virus-associated T-cell lymphoproliferative disorder. Phototest was performed with UVA and UVB, and immunohistochemical staining for CD4, CD8 and Foxp3 was conducted in both photosensitivity and lymphoma lesions. RESULTS: Phototest revealed that the action spectrum of the photosensitivity was UVB in three cases and both UVB and UVA in one case. Histopathologically, the photosensitive lesions were characterized by a lichenoid tissue reaction with a CD8+ T cell-dominant infiltrate, sharing the feature with chronic actinic dermatitis, an autoreactive photodermatosis with a cytotoxic T-cell response. Foxp3+ regulatory T cells (Tregs) were decreased in the photosensitivity lesions compared with the lymphoma lesions. CONCLUSION: Increased incidence of photosensitivity reaction was observed during Mog treatment. Decreased number of Tregs in the lesional skin suggests that this reaction is possibly induced by autoreactive cytotoxic T cells.

Type-1 polarised dendritic cells are a potent immunogen against Mycobacterium tuberculosis.

OBJECTIVE: Application of immunotherapy using dendritic cells (DCs) is considered an effective treatment strategy against persistent Mycobacterium tuberculosis infection. With the goal of developing improved therapeutic vaccination strategies for patients with tuberculosis (TB), we tested the ability of ex vivo-generated DCs to induce an effective TB antigen-specific type-1 immune response. METHODS: Monocyte-derived DCs from TB patients were induced to mature using a 'standard' cytokine cocktail (interleukin [IL] 1ß, tumour necrosis factor alpha [TNF-α], IL-6 and prostaglandin E2) or a type 1-polarised DC (DC1) cocktail (IL-1ß, TNF-α, interferon [IFN] α, IFN-γ and polyinosinic:polycytidylic acid), and were loaded with the established TB antigen 6-kDa early secretory antigenic target protein (ESAT-6). RESULTS: Although DC1s from TB patients expressed the same levels of multiple co-stimulatory molecules (CD83, CD86, CD80 and CD40) as the standard DCs (sDCs), DC1s secreted substantially higher levels of IL-12p70. Furthermore, when DCs pulsed with or without ESAT-6 were cultured with lymphocytes from the same patients, DC1s induced much higher numbers of ESAT-6-specific IFN-γ-producing T-cells than sDCs, as manifested by their superior induction of natural killer cell activation and antigen-independent suppression of regulatory T-cells. CONCLUSION: TB antigen-loaded DC1s are potent inducers of antigen-specific T-cells, which could be used to develop improved immunotherapies of TB.

Involvement of alpha-PAK-interacting exchange factor in the PAK1-c-Jun NH(2)-terminal kinase 1 activation and apoptosis induced by benzo[a]pyrene.

Benzo[a]pyrene [B(a)P], a potent procarcinogen found in combustion products such as diesel exhaust and cigarette smoke, has been recently shown to activate the c-Jun NH(2)-terminal kinase 1 (JNK1) and induce caspase-3-mediated apoptosis in Hepa1c1c7 cells. However, the molecules of the signaling pathway that control the mitogen-activated protein kinase cascades induced by B(a)P and the interaction between those and apoptosis by B(a)P have not been well defined. We report here that B(a)P promoted Cdc42/Rac1, p21-activated kinase 1 (PAK1), and JNK1 activities in 293T and HeLa cells. Moreover, alpha-PAK-interacting exchange factor (alpha PIX) mRNA and its protein expression were upregulated by B(a)P. While overexpression of an active mutant of alpha PIX (DeltaCH) facilitated B(a)P-induced activation of Cdc42/Rac1, PAK1, and JNK1, overexpression of mutated alphaPIX (L383R, L384S), which lacks guanine nucleotide exchange factor activity, SH3 domain-deleted alphaPIX (Delta SH3), which lacks the ability to bind PAK, kinase-negative PAK1 (K299R), and kinase-negative SEK1 (K220A, K224L) inhibited B(a)P-triggered JNK1 activation. Interestingly, overexpression of alphaPIX (Delta CH) and a catalytically active mutant PAK1 (T423E) accelerated B(a)P-induced apoptosis in HeLa cells, whereas alphaPIX (Delta SH3), PAK1 (K299R), and SEK 1 (K220A, K224L) inhibited B(a)P-initiated apoptosis. Finally, a preferential caspase inhibitor, Z-Asp-CH2-DCB, strongly blocked the alphaPIX (Delta CH)-enhanced apoptosis in cells treated with B(a)P but did not block PAK1/JNK1 activation. Taken together, these results indicate that alphaPIX plays a crucial role in B(a)P-induced apoptosis through activation of the JNK1 pathway kinases.

[Management of medical practice at home].

We present here how medical practice is managed at the patients home. Medical care at home is conducted in conjunction with a variety of professionals who provide health care in the community. The use of computers allows us to easily download information, and transfer it from the clinic to community services. Fluid replacement, total parenteral nutrition, palliative treatment of pain in cancer patients, management of urethral catheters, and other skills that are carried out at home would be stated.

[A study of antigenic characterization of Tamm-Horsfall glycoprotein using monoclonal antibodies].

Monoclonal antibodies (Mo-Abs) were prepared by fusing mouse myeloma cells (PAI) with spleen cells of mice immunized with Tamm-Horsfall glycoprotein (THGP). Six Mo-Abs screened for the presence of anti-THGP antibodies by enzyme linked immunosorbent assay and by immunoblotting assay have been produced. The specificity studies clearly indicated that the Mo-Ab individualized four distinct epitopes. The immunofluorescent reaction by the Mo-Abs have been analyzed in the human kidney section with normal or a minimal change. The No. 1, 2, 3 and 5 of Mo-Abs reacted with the cytoplasm of distal convoluted renal tubules, while the No. 4 and 6 of Mo-Abs reacted with a substance in the capsular space as well as with the cytoplasm of distal convoluted tubules. The sites of synthesis of this substance, detected in the capsular space by No. 4 and 6 of Mo-Abs and held the immunological cross-reactivity with tubular THGP, is presently uncertain. The specificity of the Mo-Ab may be of considerable value for further studies.

Biosynthesis of leupeptin. II Purification and properties of leupeptin acid synthetase.

An enzyme which condenses acetyl-L-leucyl-L-leucine and L-arginine into acetyl-L-leucyl-L-leucyl-L-leucyl-L-arginine (leupeptin acid) was partially purified from a cell extract of Streptomyces roseus MA839-A1. With respect to this catalytic activity, the enzyme showed the following characteristics: ATP is essential; optimum pH is 9.5; the activity is inhibited either by EDTA or pyrophosphate or N-ethylmaleimide. The molecular weight of the enzyme is about 260,000 daltons. It also catalyzes some other extension reactions, such as, acetyl-L-leucine+L-leucine+L-arginine leads to leupeptin acid, and acetyl-L-leucine+L-leucine leads to acetyl-L-leucyl-L-leucine, but neither L-leucine+L-arginine leads to (L-leucyl)1--2-L-argining, nor acetyl-L-leucine+L-arginine leads to acetyl-L-leucyl-L-arginine. ATP-PPi exchange, catalyzed by this enzyme, proceeds with either acetyl-L-leucine, or acetyl-L-leucyl-L-leucine or L-leucine, but not with acetate or arginine.